Compounds and methods for the targeted degradation of enhancer of zeste homolog 2 polypeptide

ABSTRACT

The present disclosure relates to bifunctional compounds, which find utility as modulators of enhancer of zeste homolog 2 (target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a Von Hippel-Lindau, cereblon, Inhibitors of Apotosis Proteins or mouse double-minute homolog 2 ligand which binds to the respective E3 ubiquitin ligase and on the other end a moiety which binds the target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present disclosure is a continuation of U.S. patent application Ser.No. 15/851,053, filed 21 Dec. 2017, Published as U.S. Patent ApplicationPublication No. 2018/0177750 A1, which claims priority to and thebenefit of U.S. Provisional Application No. 62/438,998, filed 24 Dec.2016, titled COMPOUNDS AND METHODS FOR THE TARGETED DEGRADATION OFENHANCER OF ZESTE HOMOLOG 2 POLYPEPTIDE, each of which are incorporatedherein by reference in its entirety for all purposes.

INCORPORATION BY REFERENCE

U.S. patent application Ser. No. 15/230,354, filed on Aug. 5, 2016; andU.S. patent application Ser. No. 15/206,497 filed 11 Jul. 2016; and U.S.patent application Ser. No. 15/209,648 filed 13 Jul. 2016; and U.S.patent application Ser. No. 15/730,728, filed on Oct. 11, 2017; and U.S.patent application Ser. No. 14/686,640, filed on Apr. 14, 2015,published as U.S. Patent Application Publication No. 2015/0291562; andU.S. patent application Ser. No. 14/792,414, filed on Jul. 6, 2015,published as U.S. Patent Application Publication No. 2016/0058872; andU.S. patent application Ser. No. 14/371,956, filed on Jul. 11, 2014,published as U.S. Patent Application Publication No. 2014/0356322; andU.S. patent application Ser. No. 15/074,820, filed on Mar. 18, 2016,published as U.S. Patent Application Publication No. 2016/0272639, areincorporated herein by reference in their entirety. Furthermore, allreferences cited herein are incorporated by reference herein in theirentirety.

FIELD OF THE INVENTION

The description provides bifunctional compounds comprising a targetprotein binding moiety and a E3 ubiquitin ligase binding moiety, andassociated methods of use. The bifunctional compounds are useful asmodulators of targeted ubiquitination, especially with respect toenhancer of zeste homolog 2 protein (EZH2), which is degraded and/orotherwise inhibited by bifunctional compounds according to the presentdisclosure.

BACKGROUND

Most small molecule drugs bind enzymes or receptors in tight andwell-defined pockets. On the other hand, protein-protein interactionsare notoriously difficult to target using small molecules due to theirlarge contact surfaces and the shallow grooves or flat interfacesinvolved. E3 ubiquitin ligases (of which hundreds are known in humans)confer substrate specificity for ubiquitination, and therefore, are moreattractive therapeutic targets than general proteasome inhibitors due totheir specificity for certain protein substrates. The development ofligands of E3 ligases has proven challenging, in part due to the factthat they must disrupt protein-protein interactions. However, recentdevelopments have provided specific ligands which bind to these ligases.For example, since the discovery of nutlins, the first small molecule E3ligase inhibitors, additional compounds have been reported that targetE3 ligases but the field remains underdeveloped. For example, since thediscovery of Nutlins, the first small molecule E3 ligase mouse doubleminute 2 homolog (MDM2) inhibitors, additional compounds have beenreported that target MDM2 (i.e., human double minute 2 or HDM2) E3ligases (J. Di, et al. Current Cancer Drug Targets (2011), 11(8),987-994).

Tumor suppressor gene p53 plays an important role in cell growth arrestand apoptosis in response to DNA damage or stress (A. Vazquez, et al.Nat. Rev. Drug. Dis. (2008), 7, 979-982), and inactivation of p53 hasbeen suggested as one of the major pathway for tumor cell survival (A.J. Levine, et al. Nature (2000), 408, 307-310). In cancer patients,about 50% were found with p53 mutation (M. Hollstein, et al. Science(1991), 233, 49-53), while patients with wild type p53 were often foundp53 down regulation by MDM2 through the protein-protein interaction ofp53 and MDM2 (P. Chene, et al. Nat. Rev. Cancer (2003), 3, 102-109).Under normal cell condition without oncogenic stress signal, MDM2 keepsp53 at low concentration. In response to DNA damage or cellular stress,p53 level increases, and that also causes increase in MDM2 due to thefeedback loop from p53/MDM2 auto regulatory system. In other words, p53regulates MDM2 at the transcription level, and MDM2 regulates p53 at itsactivity level (A. J. Levine, et al. Genes Dev. (1993) 7, 1126-1132).

Several mechanisms can explain p53 down regulation by MDM2. First, MDM2binds to N-terminal domain of p53 and blocks expression ofp53-responsive genes (J. Momand, et al. Cell (1992), 69, 1237-1245).Second, MDM2 shuttles p53 from nucleus to cytoplasm to facilitateproteolytic degradation (J. Roth, et al. EMBO J. (1998), 17, 554-564).Lastly, MDM2 carries intrinsic E3 ligase activity of conjugatingubiquitin to p53 for degradation through ubiquitin-dependent 26sproteasome system (UPS) (Y. Haupt, et al. Nature (1997) 387, 296-299).As such, because MDM2 functions as E3 ligase, recruiting MDM2 to adisease causing protein and effectuating its ubiquitination anddegradation is an approach of high interest for drug discovery.

One E3 ligase with exciting therapeutic potential is the vonHippel-Lindau (VHL) tumor suppressor, the substrate recognition subunitof the E3 ligase complex VCB, which also consists of elongins B and C,Cul2 and Rbx1. The primary substrate of VHL is Hypoxia Inducible Factor1α (HIF-1α), a transcription factor that upregulates genes such as thepro-angiogenic growth factor VEGF and the red blood cell inducingcytokine erythropoietin in response to low oxygen levels. The firstsmall molecule ligands of Von Hippel Lindau (VHL) to the substraterecognition subunit of the E3 ligase were generated, and crystalstructures were obtained confirming that the compound mimics the bindingmode of the transcription factor HIF-1α, the major substrate of VHL.

Cereblon is a protein that in humans is encoded by the CRBN gene. CRBNorthologs are highly conserved from plants to humans, which underscoresits physiological importance. Cereblon forms an E3 ubiquitin ligasecomplex with damaged DNA binding protein 1 (DDB1), Cullin-4A (CUL4A),and regulator of cullins 1 (ROC1). This complex ubiquitinates a numberof other proteins. Through a mechanism which has not been completelyelucidated, cereblon ubquitination of target proteins results inincreased levels of fibroblast growth factor 8 (FGF8) and fibroblastgrowth factor 10 (FGF10). FGF8 in turn regulates a number ofdevelopmental processes, such as limb and auditory vesicle formation.The net result is that this ubiquitin ligase complex is important forlimb outgrowth in embryos. In the absence of cereblon, DDB1 forms acomplex with DDB2 that functions as a DNA damage-binding protein.

Inhibitors of Apoptosis Proteins (IAPs) are a protein family involved insuppressing apoptosis, i.e. cell death. The human IAP family includes 8members, and numerous other organisms contain IAP homologs. IAPs containan E3 ligase specific domain and baculoviral IAP repeat (BIR) domainsthat recognize substrates, and promote their ubiquitination. IAPspromote ubiquitination and can directly bind and inhibit caspases.Caspases are proteases (e.g. caspase-3, caspase-7 and caspace-9) thatimplement apoptosis. As such, through the binding of caspases, IAPsinhibit cell death. However, pro-apoptotic stimuli can result in therelease of mitochondrial proteins DIABLO (also known as secondmitochondria-derived activator of caspases or SMAC) and HTRA2 (alsoknown as Omi). Binding of DIABLO and HTRA2 appears to block IAPactivity.

SMAC interacts with essentially all known IAPs including XIAP, c-IAP1,c-IAP2, NIL-IAP, Bruce, and survivin. The first four amino acids (AVPI)of mature SMAC bind to a portion of IAPs, which is believed to beessential for blocking the anti-apoptotic effects of IAPs.

Bifunctional compounds such as those that are described in U.S. PatentApplication Publications 2015-0291562 and 2014-0356322 (incorporatedherein by reference), function to recruit endogenous proteins to an E3ubiquitin ligase for degradation. In particular, the publicationsdescribe bifunctional or proteolysis targeting chimeric (PROTAC)compounds, which find utility as modulators of targeted ubiquitinationof a variety of polypeptides and other proteins, which are then degradedand/or otherwise inhibited by the bifunctional compounds.

An ongoing need exists in the art for effective treatments for diseaseassociated with overexpression or aggregation of enhancer of zestehomolog 2 (EZH2). However, non-specific effects, and the inability totarget and modulate EXH2, remain as obstacles to the development ofeffective treatments. As such, small-molecule therapeutic agents thattarget EZH2 and that leverage or potentiate VHL's, cereblon's, MDM2's,and IAPs' substrate specificity would be very useful.

SUMMARY

The present disclosure describes bifunctional compounds which functionto recruit endogenous proteins to an E3 ubiquitin ligase fordegradation, and methods of using the same. In particular, the presentdisclosure provides bifunctional or proteolysis targeting chimeric(PROTAC) compounds, which find utility as modulators of targetedubiquitination of a variety of polypeptides and other proteins, whichare then degraded and/or otherwise inhibited by the bifunctionalcompounds as described herein. An advantage of the compounds providedherein is that a broad range of pharmacological activities is possible,consistent with the degradation/inhibition of targeted polypeptides fromvirtually any protein class or family. In addition, the descriptionprovides methods of using an effective amount of the compounds asdescribed herein for the treatment or amelioration of a diseasecondition, such as cancer, e.g., breast cancer, prostate cancer, bladdercancer, uterine cancer, renal cancer, melanoma, and/or lymphoma.

As such, in one aspect the disclosure provides bifunctional or PROTACcompounds, which comprise an E3 ubiquitin ligase binding moiety (i.e., aligand for an E3 ubquitin ligase or “ULM” group), and a moiety thatbinds a target protein (i.e., a protein/polypeptide targeting ligand or“PTM” group) such that the target protein/polypeptide is placed inproximity to the ubiquitin ligase to effect degradation (and inhibition)of that protein, such as enhancer of zeste homolog 2 (EZH2). In apreferred embodiment, the ULM (ubiquitination ligase modulator) can beVon Hippel-Lindau E3 ubiquitin ligase (VHL) binding moiety (VLM), or acereblon E3 ubiquitin ligase binding moiety (CLM), or a mouse doubleminute 2 homolog (MDM2) E3 ubiquitin ligase binding moiety (MLM), or anIAP E3 ubiquitin ligase binding moiety (i.e., a “ILM”), or a combinationthereof. For example, the structure of the bifunctional compound can bedepicted as:

The respective positions of the PTM and ULM moieties (e.g., VLM, CLM,MLM or ILM) as well as their number as illustrated herein is provided byway of example only and is not intended to limit the compounds in anyway. As would be understood by the skilled artisan, the bifunctionalcompounds as described herein can be synthesized such that the numberand position of the respective functional moieties can be varied asdesired.

In certain embodiments, the bifunctional compound further comprises achemical linker (“L”). In this example, the structure of thebifunctional compound can be depicted as:

wherein PTM is a protein/polypeptide targeting moiety, L is a linker,e.g., a bond or a chemical group coupling PTM to ULM, and ULM is a IAPE3 ubiquitin ligase binding moiety, or a Von Hippel-Lindau E3 ubiquitinligase (VHL) binding moiety (VLM), or a cereblon E3 ubiquitin ligasebinding moiety (CLM), or a mouse double minute 2 homolog (MDM2) E3ubiquitin ligase binding moiety (MLM).

For example, the structure of the bifunctional compound can be depictedas:

wherein: PTM is a protein/polypeptide targeting moiety; “L” is a linker(e.g. a bond or a chemical linker group) coupling the PTM and at leastone of VLM, CLM, MLM, ILM, or a combination thereof; VLM is VonHippel-Lindau E3 ubiquitin ligase binding moiety that binds to VHL E3ligase; CLM is cereblon E3 ubiquitin ligase binding moiety that binds tocereblon; MLM is an MDM2 E3 ubiquitin ligase binding moiety; and ILM isa IAP binding moiety which binds to IAP.

In certain preferred embodiments, the ILM is an AVPI tetrapeptidefragment. As such, in certain additional embodiments, the ILM of thebifunctional compound comprises the amino acids alanine (A), valine (V),proline (P), and isoleucine (I) or their unnatural mimetics,respectively. In additional embodiments, the amino acids of the AVPItetrapeptide fragment are connected to each other through amide bonds(i.e., —C(O)NH— or —NHC(O)—).

In certain embodiments, the compounds as described herein comprisemultiple independently selected ULMs, multiple PTMs, multiple chemicallinkers or a combination thereof.

In certain embodiments, ILM comprises chemical moieties such as thosedescribed herein.

In additional embodiments, VLM can be hydroxyproline or a derivativethereof. Furthermore, other contemplated VLMs are included in U.S.Patent Application Publication No. 2014/03022523, which as discussedabove, is incorporated herein in its entirety.

In an embodiment, the CLM comprises a chemical group derived from animide, a thioimide, an amide, or a thioamide. In a particularembodiment, the chemical group is a phthalimido group, or an analog orderivative thereof. In a certain embodiment, the CLM is thalidomide,lenalidomide, pomalidomide, analogs thereof, isosteres thereof, orderivatives thereof. Other contemplated CLMs are described in U.S.Patent Application Publication No. 2015/0291562, which is incorporatedherein in its entirety.

In certain embodiments, MLM can be nutlin or a derivative thereof.Furthermore, other contemplated MLMs are included in U.S. patentapplication Ser. No. 15/206,497, filed 11 Jul. 2016, which as discussedabove, is incorporated herein in its entirety. In certain additionalembodiments, the MLM of the bifunctional compound comprises chemicalmoieties such as substituted imidazolines, substitutedspiro-indolinones, substituted pyrrolidines, substituted piperidinones,substituted morpholinones, substituted pyrrolopyrimidines, substitutedimidazolopyridines, substituted thiazoloimidazoline, substitutedpyrrolopyrrolidinones, and substituted isoquinolinones.

In additional embodiments, the MLM comprises the core structuresmentioned above with adjacent bis-aryl substitutions positioned as cis-or trans-configurations.

In certain embodiments, “L” is a bond. In additional embodiments, thelinker “L” is a connector with a linear non-hydrogen atom number in therange of 1 to 20. The connector “L” can contain, but not limited to thefunctional groups such as ether, amide, alkane, alkene, alkyne, ketone,hydroxyl, carboxylic acid, thioether, sulfoxide, and sulfone. The linkercan contain aromatic, heteroaromatic, cyclic, bicyclic and tricyclicmoieties. Substitution with halogen, such as Cl, F, Br and I can beincluded in the linker. In the case of fluorine substitution, single ormultiple fluorines can be included.

In certain embodiments, VLM is a derivative of trans-3-hydroxyproline,where both nitrogen and carboxylic acid in trans-3-hydroxyproline arefunctionalized as amides.

In certain embodiments, CLM is a derivative of piperidine-2,6-dione,where piperidine-2,6-dione can be substituted at the 3-position, and the3-substitution can be bicyclic hetero-aromatics with the linkage as C—Nbond or C—C bond. Examples of CLM can be, but not limited to,pomalidomide, lenalidomide and thalidomide and their derivatives.

In an additional aspect, the description provides therapeuticcompositions comprising an effective amount of a compound as describedherein or salt form thereof, and a pharmaceutically acceptable carrier.The therapeutic compositions modulate protein degradation in a patientor subject, for example, an animal such as a human, and can be used fortreating or ameliorating disease states or conditions which aremodulated through the degraded protein. In certain embodiments, thetherapeutic compositions as described herein may be used to effectuatethe degradation of proteins of interest for the treatment oramelioration of a disease, e.g., cancer. In yet another aspect, thepresent disclosure provides a method of ubiquitinating/degrading atarget protein in a cell. In certain embodiments, the method comprisesadministering a bifunctional compound as described herein comprising anILM and a PTM, a PTM and a VLM, or a PTM and a CLM, or a PTM and a MLM,preferably linked through a linker moiety, as otherwise describedherein, wherein the VLM/ILM/CLM/MLM is coupled to the PTM through alinker to target protein that binds to PTM for degradation. Similarly,the PTM can be coupled to VLM or CLM or MLM or ILM through a linker totarget a protein or polypeptide for degradation. Degradation of thetarget protein will occur when the target protein is placed in proximityto the E3 ubiquitin ligase, thus resulting in degradation/inhibition ofthe effects of the target protein and the control of protein levels. Thecontrol of protein levels afforded by the present disclosure providestreatment of a disease state or condition, which is modulated throughthe target protein by lowering the level of that protein in the cells ofa patient.

In still another aspect, the description provides methods for treatingor ameliorating a disease, disorder or symptom thereof in a subject or apatient, e.g., an animal such as a human, comprising administering to asubject in need thereof a composition comprising an effective amount,e.g., a therapeutically effective amount, of a compound as describedherein or salt form thereof, and a pharmaceutically acceptable carrier,wherein the composition is effective for treating or ameliorating thedisease or disorder or symptom thereof in the subject.

In another aspect, the description provides methods for identifying theeffects of the degradation of proteins of interest in a biologicalsystem using compounds according to the present disclosure.

The preceding general areas of utility are given by way of example onlyand are not intended to be limiting on the scope of the presentdisclosure and appended claims. Additional objects and advantagesassociated with the compositions, methods, and processes of the presentdisclosure will be appreciated by one of ordinary skill in the art inlight of the instant claims, description, and examples. For example, thevarious aspects and embodiments of the disclosure may be utilized innumerous combinations, all of which are expressly contemplated by thepresent description. These additional aspects and embodiments areexpressly included within the scope of the present disclosure. Thepublications and other materials used herein to illuminate thebackground of the disclosure, and in particular cases, to provideadditional details respecting the practice, are incorporated byreference.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are incorporated into and form a partof the specification, illustrate several embodiments of the presentdisclosure and, together with the description, serve to explain theprinciples of the disclosure. The drawings are only for the purpose ofillustrating an embodiment of the disclosure and are not to be construedas limiting the disclosure. Further objects, features and advantages ofthe disclosure will become apparent from the following detaileddescription taken in conjunction with the accompanying figures showingillustrative embodiments of the disclosure, in which:

FIGS. 1A and 1B. Illustration of general principle for PROTAC function.(A) Exemplary PROTACs comprise a protein targeting moiety (PTM; darklyshaded rectangle), a ubiquitin ligase binding moiety (ULM; lightlyshaded triangle), and optionally a linker moiety (L; black line)coupling or tethering the PTM to the ULM. (B) Illustrates the functionaluse of the PROTACs as described herein. Briefly, the ULM recognizes andbinds to a specific E3 ubiquitin ligase, and the PTM binds and recruitsa target protein bringing it into close proximity to the E3 ubiquitinligase. Typically, the E3 ubiquitin ligase is complexed with an E2ubiquitin-conjugating protein, and either alone or via the E2 proteincatalyzes attachment of ubiquitin (dark circles) to a lysine on thetarget protein via an isopeptide bond. The poly-ubiquitinated protein(far right) is then targeted for degradation by the proteosomalmachinery of the cell.

DETAILED DESCRIPTION

The following is a detailed description provided to aid those skilled inthe art in practicing the present disclosure. Those of ordinary skill inthe art may make modifications and variations in the embodimentsdescribed herein without departing from the spirit or scope of thepresent disclosure. All publications, patent applications, patents,figures and other references mentioned herein are expressly incorporatedby reference in their entirety.

Presently described are compositions and methods that relate to thesurprising and unexpected discovery that an E3 ubiquitin ligase protein(e.g., inhibitors of apoptosis proteins (IAP), a Von Hippel-Lindau E3ubiquitin ligase (VHL), a cereblon E3 ubiquitin ligase, or a mousedouble minute 2 homolog (MDM2) E3 ubiquitin ligase) ubiquitinates atarget protein once it and the target protein are placed in proximity bya bifunctional or chimeric construct that binds the E3 ubiquitin ligaseprotein and the target protein (such as enhancer of zeste homolog 2[EZH2]). Accordingly the present disclosure provides such compounds andcompositions comprising an E3 ubiquitin ligase binding moiety (“ULM”)coupled to a protein target binding moiety (“PTM”), which result in theubiquitination of a chosen target protein, which leads to degradation ofthe target protein by the proteasome (see FIG. 1 ). The presentdisclosure also provides a library of compositions and the use thereof.

In certain aspects, the present disclosure provides compounds whichcomprise a ligand, e.g., a small molecule ligand (i.e., having amolecular weight of below 2,000, 1,000, 500, or 200 Daltons), which iscapable of binding to a ubiquitin ligase, such as IAP, VHL, MDM2, orcereblon. The compounds also comprise a moiety that is capable ofbinding to target protein, in such a way that the target protein isplaced in proximity to the ubiquitin ligase to effect degradation(and/or inhibition) of that protein. Small molecule can mean, inaddition to the above, that the molecule is non-peptidyl, that is, it isnot generally considered a peptide, e.g., comprises fewer than 4, 3, or2 amino acids. In accordance with the present description, the PTM, ULMor PROTAC molecule can be a small molecule.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this disclosure belongs. The terminology used in thedescription is for describing particular embodiments only and is notintended to be limiting of the disclosure.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise (such as in the case of a groupcontaining a number of carbon atoms in which case each carbon atomnumber falling within the range is provided), between the upper andlower limit of that range and any other stated or intervening value inthat stated range is encompassed within the disclosure. The upper andlower limits of these smaller ranges may independently be included inthe smaller ranges is also encompassed within the disclosure, subject toany specifically excluded limit in the stated range. Where the statedrange includes one or both of the limits, ranges excluding either bothof those included limits are also included in the disclosure.

The following terms are used to describe the present disclosure. Ininstances where a term is not specifically defined herein, that term isgiven an art-recognized meaning by those of ordinary skill applying thatterm in context to its use in describing the present disclosure.

The articles “a” and “an” as used herein and in the appended claims areused herein to refer to one or to more than one (i.e., to at least one)of the grammatical object of the article unless the context clearlyindicates otherwise. By way of example, “an element” means one elementor more than one element.

The phrase “and/or,” as used herein in the specification and in theclaims, should be understood to mean “either or both” of the elements soconjoined, i.e., elements that are conjunctively present in some casesand disjunctively present in other cases. Multiple elements listed with“and/or” should be construed in the same fashion, i.e., “one or more” ofthe elements so conjoined. Other elements may optionally be presentother than the elements specifically identified by the “and/or” clause,whether related or unrelated to those elements specifically identified.Thus, as a non-limiting example, a reference to “A and/or B”, when usedin conjunction with open-ended language such as “comprising” can refer,in one embodiment, to A only (optionally including elements other thanB); in another embodiment, to B only (optionally including elementsother than A); in yet another embodiment, to both A and B (optionallyincluding other elements); etc.

As used herein in the specification and in the claims, “or” should beunderstood to have the same meaning as “and/or” as defined above. Forexample, when separating items in a list, “or” or “and/or” shall beinterpreted as being inclusive, i.e., the inclusion of at least one, butalso including more than one, of a number or list of elements, and,optionally, additional unlisted items. Only terms clearly indicated tothe contrary, such as “only one of” or “exactly one of,” or, when usedin the claims, “consisting of,” will refer to the inclusion of exactlyone element of a number or list of elements. In general, the term “or”as used herein shall only be interpreted as indicating exclusivealternatives (i.e., “one or the other but not both”) when preceded byterms of exclusivity, such as “either,” “one of,” “only one of,” or“exactly one of.”

In the claims, as well as in the specification above, all transitionalphrases such as “comprising,” “including,” “carrying,” “having,”“containing,” “involving,” “holding,” “composed of,” and the like are tobe understood to be open-ended, i.e., to mean including but not limitedto. Only the transitional phrases “consisting of” and “consistingessentially of” shall be closed or semi-closed transitional phrases,respectively, as set forth in the United States Patent Office Manual ofPatent Examining Procedures, Section 2111.03.

As used herein in the specification and in the claims, the phrase “atleast one,” in reference to a list of one or more elements, should beunderstood to mean at least one element selected from anyone or more ofthe elements in the list of elements, but not necessarily including atleast one of each and every element specifically listed within the listof elements and not excluding any combinations of elements in the listof elements. This definition also allows that elements may optionally bepresent other than the elements specifically identified within the listof elements to which the phrase “at least one” refers, whether relatedor unrelated to those elements specifically identified. Thus, as anonlimiting example, “at least one of A and B” (or, equivalently, “atleast one of A or B,” or, equivalently “at least one of A and/or B”) canrefer, in one embodiment, to at least one, optionally including morethan one, A, with no B present (and optionally including elements otherthan B); in another embodiment, to at least one, optionally includingmore than one, B, with no A present (and optionally including elementsother than A); in yet another embodiment, to at least one, optionallyincluding more than one, A, and at least one, optionally including morethan one, B (and optionally including other elements); etc.

It should also be understood that, in certain methods described hereinthat include more than one step or act, the order of the steps or actsof the method is not necessarily limited to the order in which the stepsor acts of the method are recited unless the context indicatesotherwise.

The terms “co-administration” and “co-administering” or “combinationtherapy” refer to both concurrent administration (administration of twoor more therapeutic agents at the same time) and time variedadministration (administration of one or more therapeutic agents at atime different from that of the administration of an additionaltherapeutic agent or agents), as long as the therapeutic agents arepresent in the patient to some extent, preferably at effective amounts,at the same time. In certain preferred aspects, one or more of thepresent compounds described herein, are coadministered in combinationwith at least one additional bioactive agent, especially including ananticancer agent. In particularly preferred aspects, theco-administration of compounds results in synergistic activity and/ortherapy, including anticancer activity.

The term “compound”, as used herein, unless otherwise indicated, refersto any specific chemical compound disclosed herein and includestautomers, regioisomers, geometric isomers, and where applicable,stereoisomers, including optical isomers (enantiomers) and otherstereoisomers (diastereomers) thereof, as well as pharmaceuticallyacceptable salts and derivatives, including prodrug and/or deuteratedforms thereof where applicable, in context. Deuterated small moleculescontemplated are those in which one or more of the hydrogen atomscontained in the drug molecule have been replaced by deuterium.

Within its use in context, the term compound generally refers to asingle compound, but also may include other compounds such asstereoisomers, regioisomers and/or optical isomers (including racemicmixtures) as well as specific enantiomers or enantiomerically enrichedmixtures of disclosed compounds. The term also refers, in context toprodrug forms of compounds which have been modified to facilitate theadministration and delivery of compounds to a site of activity. It isnoted that in describing the present compounds, numerous substituentsand variables associated with same, among others, are described. It isunderstood by those of ordinary skill that molecules which are describedherein are stable compounds as generally described hereunder. When thebond is shown, both a double bond and single bond are represented orunderstood within the context of the compound shown and well-known rulesfor valence interactions.

The term “ubiquitin ligase” refers to a family of proteins thatfacilitate the transfer of ubiquitin to a specific substrate protein,targeting the substrate protein for degradation. For example, IAP an E3ubiquitin ligase protein that alone or in combination with an E2ubiquitin-conjugating enzyme causes the attachment of ubiquitin to alysine on a target protein, and subsequently targets the specificprotein substrates for degradation by the proteasome. Thus, E3 ubiquitinligase alone or in complex with an E2 ubiquitin conjugating enzyme isresponsible for the transfer of ubiquitin to targeted proteins. Ingeneral, the ubiquitin ligase is involved in polyubiquitination suchthat a second ubiquitin is attached to the first; a third is attached tothe second, and so forth. Polyubiquitination marks proteins fordegradation by the proteasome. However, there are some ubiquitinationevents that are limited to mono-ubiquitination, in which only a singleubiquitin is added by the ubiquitin ligase to a substrate molecule.Mono-ubiquitinated proteins are not targeted to the proteasome fordegradation, but may instead be altered in their cellular location orfunction, for example, via binding other proteins that have domainscapable of binding ubiquitin. Further complicating matters, differentlysines on ubiquitin can be targeted by an E3 to make chains. The mostcommon lysine is Lys48 on the ubiquitin chain. This is the lysine usedto make polyubiquitin, which is recognized by the proteasome.

The term “patient” or “subject” is used throughout the specification todescribe an animal, preferably a human or a domesticated animal, to whomtreatment, including prophylactic treatment, with the compositionsaccording to the present disclosure is provided. For treatment of thoseinfections, conditions or disease states which are specific for aspecific animal such as a human patient, the term patient refers to thatspecific animal, including a domesticated animal such as a dog or cat ora farm animal such as a horse, cow, sheep, etc. In general, in thepresent disclosure, the term patient refers to a human patient unlessotherwise stated or implied from the context of the use of the term.

The term “effective” is used to describe an amount of a compound,composition or component which, when used within the context of itsintended use, effects an intended result. The term effective subsumesall other effective amount or effective concentration terms, which areotherwise described or used in the present application.

Compounds and Compositions

In one aspect, the description provides compounds comprising an E3ubiquitin ligase binding moiety (“ULM”) that is an IAP E3 ubiquitinligase binding moiety (an “ILM”), a cereblon E3 ubiquitin ligase bindingmoiety (a “CLM”), a Von Hippel-Lindae E3 ubiquitin ligase (VHL) bindingmoiety (VLM), and/or a mouse double minute 2 homologue (MDM2) E3ubiquitin ligase binding moiety (MLM). In an exemplary embodiment, theULM is coupled to a target protein binding moiety (PTM) via a chemicallinker (L) according to the structure:PTM-L-ULM  (A)wherein L is a bond or a chemical linker group, ULM is a E3 ubiquitinligase binding moiety, and PTM is a target protein binding moiety. Thenumber and/or relative positions of the moieties in the compoundsillustrated herein is provided by way of example only. As would beunderstood by the skilled artisan, compounds described herein can besynthesized with any desired number and/or relative position of therespective functional moieties.

The terms ULM, ILM, VLM, MLM, and CLM are used in their inclusive senseunless the context indicates otherwise. For example, the term ULM isinclusive of all ULMs, including those that bind IAP (i.e., ILMs), MDM2(i.e., MLM), cereblon (i.e., CLM), and VHL (i.e., VLM). Further, theterm ILM is inclusive of all possible IAP E3 ubiquitin ligase bindingmoieties, the term MLM is inclusive of all possible MDM2 E3 ubiquitinligase binding moieties, the term VLM is inclusive of all possible VHLbinding moieties, and the term CLM is inclusive of all cereblon bindingmoieties.

In another aspect, the present disclosure provides bifunctional ormultifunctional compounds (e.g., PROTACs) useful for regulating proteinactivity by inducing the degradation of a target protein. In certainembodiments, the compound comprises an ILM or a VLM or a CLM or a MLMcoupled, e.g., linked covalently, directly or indirectly, to a moietythat binds a target protein (i.e., a protein targeting moiety or a“PTM”). In certain embodiments, the ILM/VLM/CLM/MLM and PTM are joinedor coupled via a chemical linker (L). The ILM binds the IAP E3 ubiquitinligase, the VLM binds VHL, CLM binds the cereblon E3 ubiquitin ligase,and MLM binds the MDM2 E3 ubiquitin ligase, and the PTM recognizes atarget protein and the interaction of the respective moieties with theirtargets facilitates the degradation of the target protein by placing thetarget protein in proximity to the ubiquitin ligase protein. Anexemplary bifunctional compound can be depicted as:PTM-ILM  (B)PTM-CLM  (C)PTM-VLM  (D)PTM-MLM  (E)

In certain embodiments, the bifunctional compound further comprises achemical linker (“L”). For example, the bifunctional compound can bedepicted as:PTM-L-ILM  (F)PTM-L-CLM  (G)PTM-L-VLM  (H)PTM-L-MLM  (I)wherein the PTM is a protein/polypeptide targeting moiety, the L is achemical linker, the ILM is a IAP E3 ubiquitin ligase binding moiety,the CLM is a cereblon E3 ubiquitin ligase binding moiety, the VLM is aVHL binding moiety, and the MLM is a MDM2 E3 ubiquitin ligase bindingmoiety.

In certain embodiments, the ULM (e.g., a ILM, a CLM, a VLM, or a MLM)shows activity or binds to the E3 ubiquitin ligase (e.g., IAP E3ubiquitin ligase, cereblon E3 ubiquitin ligase, VHL, or MDM2 E3ubiquitin ligase) with an IC₅₀ of less than about 200 μM. The IC₅₀ canbe determined according to any method known in the art, e.g., afluorescent polarization assay.

In certain additional embodiments, the bifunctional compounds describedherein demonstrate an activity with an IC₅₀ of less than about 100, 50,10, 1, 0.5, 0.1, 0.05, 0.01, 0.005, 0.001 mM, or less than about 100,50, 10, 1, 0.5, 0.1, 0.05, 0.01, 0.005, 0.001 μM, or less than about100, 50, 10, 1, 0.5, 0.1, 0.05, 0.01, 0.005, 0.001 nM, or less thanabout 100, 50, 10, 1, 0.5, 0.1, 0.05, 0.01, 0.005, 0.001 pM.

In certain embodiments, the compounds as described herein comprisemultiple PTMs (targeting the same or different protein targets),multiple ULMs, one or more ULMs (i.e., moieties that bind specificallyto multiple/different E3 ubiquitin ligase, e.g., VHL, IAP, cereblon,and/or MDM2) or a combination thereof. In any of the aspects orembodiments described herein, the PTMs and ULMs (e.g., ILM, VLM, CLM,and/or MLM) can be coupled directly or via one or more chemical linkersor a combination thereof. In additional embodiments, where a compoundhas multiple ULMs, the ULMs can be for the same E3 ubiquintin ligase oreach respective ULM can bind specifically to a different E3 ubiquitinligase. In still further embodiments, where a compound has multiplePTMs, the PTMs can bind the same target protein or each respective PTMcan bind specifically to a different target protein.

In certain embodiments, where the compound comprises multiple ULMs, theULMs are identical. In additional embodiments, the compound comprising aplurality of ULMs (e.g., ULM, ULM′, etc.), at least one PTM coupled to aULM directly or via a chemical linker (L) or both. In certain additionalembodiments, the compound comprising a plurality of ULMs furthercomprises multiple PTMs. In still additional embodiments, the PTMs arethe same or, optionally, different. In still further embodiments,wherein the PTMs are different, the respective PTMs may bind the sameprotein target or bind specifically to a different protein target.

In certain embodiments, the compound may comprise a plurality of ULMsand/or a plurality of ULM's. In further embodiments, the compoundcomprising at least two different ULMs, a plurality of ULMs, and/or aplurality of ULM's further comprises at least one PTM coupled to a ULMor a ULM′ directly or via a chemical linker or both. In any of theembodiments described herein, a compound comprising at least twodifferent ILMs can further comprise multiple PTMs. In still additionalembodiments, the PTMs are the same or, optionally, different. In stillfurther embodiments, wherein the PTMs are different the respective PTMsmay bind the same protein target or bind specifically to a differentprotein target. In still further embodiments, the PTM itself is a ULM(or ULM′), such as an ILM, a VLM, a CLM, a MLM, an ILM′, a VLM′, a CLM′,and/or a MLM′.

In additional embodiments, the description provides the compounds asdescribed herein including their enantiomers, diastereomers, solvatesand polymorphs, including pharmaceutically acceptable salt formsthereof, e.g., acid and base salt forms.

Exemplary ILMs

AVPI Tetrapeptide Fragments

In any of the compounds described herein, the ILM can comprise analanine-valine-proline-isoleucine (AVPI) tetrapeptide fragment or anunnatural mimetic thereof. In certain embodiments, the ILM is selectedfrom the group consisting of chemical structures represented by Formulas(I), (II), (III), (IV), and (V):

wherein:

-   -   R¹ for Formulas (I), (II), (III), (IV), and (V) is selected from        H or alkyl;    -   R² for Formulas (I), (II), (III), (IV), and (V) is selected from        H or alkyl;    -   R³ for Formulas (I), (II), (III), (IV), and (V) is selected from        H, alkyl, cycloalkyl and heterocycloalkyl;    -   R⁵ and R⁶ for Formulas (I), (II), (III), (IV), and (V) are        independently selected from H, alkyl, cycloalkyl,        heterocycloalkyl, or more preferably, R⁵ and R⁶ taken together        for Formulas (I), (II), (III), (IV), and (V) form a pyrrolidine        or a piperidine ring further optionally fused to 1-2 cycloalkyl,        heterocycloalkyl, aryl or heteroaryl rings, each of which can        then be further fused to another cycloalkyl, heterocycloalkyl,        aryl or heteroaryl ring;    -   R³ and R⁵ for Formulas (I), (II), (III), (IV), and (V) taken        together can form a 5-8-membered ring further optionally fused        to 1-2 cycloalkyl, heterocycloalkyl, aryl or heteroaryl rings;    -   R⁷ for Formulas (I), (II), (III), (IV), and (V) is selected from        cycloalkyl, cycloalkylalkyl, heterocycloalkyl,        heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl or        heteroarylalkyl, each one further optionally substituted with        1-3 substituents selected from halogen, alkyl, haloalkyl,        hydroxyl, alkoxy, cyano, (hetero)cycloalkyl or (hetero)aryl, or        R⁷ is —C(O)NH—R⁴; and    -   R⁴ is selected from alkyl, cycloalkyl, heterocycloalkyl,        cycloalkylalkyl, heterocycloalkylalkyl, aryl, arylalkyl,        heteroaryl, heteroarylalkyl, further optionally substituted with        1-3 substituents as described above.

As shown above, P1, P2, P3, and P4 of Formula (II) correlate with A, V,P, and I, respectively, of the AVPI tetrapeptide fragment or anunnatural mimetic thereof. Similarly, each of Formulas (I) and (III)through (V) have portions correlating with A, V, P, and I of the AVPItetrapeptide fragment or an unnatural mimetic thereof.

In any of the compounds described herein, the ILM can have the structureof Formula (VI), which is a derivative of IAP antagonists described inWO Pub. No. 2008/014236, or an unnatural mimetic thereof:

wherein:

-   -   R₁ of Formula (VI) is, independently selected from H,        C₁-C₄-alky, C₁-C₄-alkenyl, C₁-C₄-alkynyl or C₃-C₁₀-cycloalkyl        which are unsubstituted or substituted;    -   R₂ of Formula (VI) is, independently selected from H,        C₁-C₄-alkyl, C₁-C₄-alkenyl, C₁-C₄-alkynyl or C₃-C₁₀-cycloalkyl        which are unsubstituted or substituted;    -   R₃ of Formula (VI) is, independently selected from H, —CF₃,        —C₂H₅. C₁-C₄-alkyl, C₁-C₄-alkenyl, C₁-C₄-alkynyl, —CH₂—Z or any        R₂ and R₃ together form a heterocyclic ring;    -   each Z of Formula (VI) is, independently selected from H, —OH,        F, Cl, —CH₃, —CF₃, —CH₂Cl, —CH₂F or —CH₂OH;    -   R₄ of Formula (VI) is, independently selected from C₁-C₁₆        straight or branched alkyl, C₁-C₁₆-alkenyl, C₁-C₁₆-alkynyl,        C₃-C₁₀-cycloalkyl, —(CH₂)₀₋₆Z₁, —(CH₂)₀₋₆-aryl, and        —(CH₂)₀₋₆-het, wherein alkyl, cycloalkyl, and phenyl are        unsubstituted or substituted;    -   R₅ of Formula (VI) is, independently selected from H,        C₁₋₁₀-alkyl, aryl, phenyl. C₃₋₇-cycloalkyl,        —(CH₂)₁₋₆—C₃₋₇-cycloalkyl, —C₁₋₁₀-alkyl-aryl,        —(CH₂)₀₋₆—C₃₋₇-cycloalkyl-(CH₂)₀₋₆-phenyl,        —(CH₂)₀₋₄—CH[(CH₂)₁₋₄-phenyl]₂, indanyl, —C(O)—C₁₋₁₀-alkyl,        —C(O)—(CH₂)₁₋₆—C₃₋₇-cycloalkyl, —C(O)—(CH₂)₀₋₆-phenyl,        —(CH₂)₀₋₆—C(O)-phenyl, —(CH₂)₀₋₆-het, —C(O)—(CH₂)₁₋₆-het, or R₅        is selected from a residue of an amino acid, wherein the alkyl,        cycloalkyl, phenyl, and aryl substituents are unsubstituted or        substituted;    -   Z₁ of Formula (VI) is, independently selected from        —N(R₁₀)—C(O)—C₁₋₁₀-alkyl, —N(R₁₀)—C(O)—(CH₂)₀₋₆—C₃₋₇-cycloalkyl,        —N(R₁₀)—C(O)—(CH₂)₀₋₆-phenyl, —N(R₁₀)—C(O)(CH₂)₁₋₆-het,        —C(O)—N(R₁₁)(R₁₂), —C(O)—O—C₁₋₁₀-alkyl,        —C(O)—O—(CH₂)₁₋₆—C₃₋₇-cycloalkyl, —C(O)—O—(CH₂)₀₋₆-phenyl,        —C(O)—O—(CH₂)₁₋₆-het, —O—C(O)—C₁₋₁₀-alkyl,        —O—C(O)—(CH₂)₁₋₆—C₃₋₇-cycloakyl, —O—C(O)—(CH₂)₀₋₆-phenyl,        —O—C(O)—(CH₂)₁₋₆-het, wherein alkyl, cycloalkyl, and phenyl are        unsubstituted or substituted;    -   het of Formula (VI) is, independently selected from a 5-7 member        heterocyclic ring containing 1-4 heteroatoms selected from N, O,        and S, or an 8-12 member fused ring system including at least        one 5-7 member heterocyclic ring containing 1, 2, or 3        heteroatoms selected from N, O, and S, which heterocyclic ring        or fused ring system is unsubstituted or substituted on a carbon        or nitrogen atom;    -   R₁₀ of Formula (VI) is selected from H, —CH₃, —CF₃, —CH₂OH, or        —CH₂Cl; R₁₁ and R₁₂ of Formula (VI) are independently selected        from H. C₁₋₄-alkyl, C₃₋₇-cycloalkyl, —(CH₂)₁₋₆—C₃₋₇-cycloakyl,        (CH₂)₀₋₆-phenyl, wherein alkyl, cycloalkyl, and phenyl are        unsubstituted or substituted; or R₁₁ and R₁₂ together with the        nitrogen form het, and    -   U of Formula (VI) is, independently, as shown in Formula (VII):

wherein:

-   -   each n of Formula (VII) is, independently selected from 0 to 5;    -   X of Formula (VII) is selected from the group —CH and N;    -   R_(a) and R_(b), of Formula (VII) are independently selected        from the group O, S. or N atom or C₀₋₈-alkyl wherein one or more        of the carbon atoms in the alkyl chain are optionally replaced        by a heteroatom selected from O, S, or N, and where each alkyl        is, independently, either unsubstituted or substituted;    -   R_(d) of Formula (VII) is selected from the group        Re-Q-(R_(f))_(p)(R_(g))_(q), and Ar₁-D-Ar₂;    -   R_(e) of Formula (VII) is selected from the group H or any R_(c)        and R_(d) together form a cycloalkyl or het; where if R_(c) and        R_(d) form a cycloalkyl or het, R₅ is attached to the formed        ring at a C or N atom;    -   p and q of Formula (VII) are independently selected from 0 or 1;    -   R_(e) of Formula (VII) is selected from the group C₁₋₈-alkyl and        alkylidene, and each Re is either unsubstituted or substituted;    -   Q is selected from the group N, O, S, S(O), and S(O)₂;    -   Ar₁ and Ar₂ of Formula (VII) are independently selected from the        group of substituted or unsubstituted aryl and het;    -   R_(f) and R_(g) of Formula (VII) are independently selected from        H, —C₁₋₁₀-alkyl, C₁₋₁₀-alkylaryl, —OH, —O—C₁₋₁₀-alkyl,        —(CH₂)₀₋₆—C₃₋₇-cycloalkyl, —O—(CH₂)₀₋₆-aryl, phenyl, aryl,        phenyl-phenyl, —(CH₂)₁₋₆-het, —O—(CH₂)₁₋₆-het, —OR₁₃, —C(O)—R₁₃,        —C(O)—N(R₁₃)(R₁₄), —N(R₁₃)(R₁₄). —S—R₁₃, —S(O)—R₁₃, —S(O)₂—R₁₃,        —S(O)₂—NR₁₃R₁₄, —NR₁₃—S(O)₂—R₁₄, —S—C₁₋₁₀-alkyl,        aryl-C₁₋₄-alkyl, or het-C₁₋₄-alkyl, wherein alkyl, cycloalkyl,        het, and aryl are unsubstituted or substituted, —SO₂—C₁₋₂-alkyl,        —SO₂—C₁₋₂-alkylphenyl, —O—C₁₋₄-alkyl, or any R_(g) and R_(f)        together form a ring selected from het or aryl;    -   D of Formula (VII) is selected from the group —CO—,        —C(O)—C₁₋₇-alkylene or arylene, —CF₂—, —O—, —S(O)_(r) where r is        0-2, 1,3-dioxalane, or C₁₋₇-alkyl-OH; where alkyl, alkylene, or        arylene are unsubstituted or substituted with one or more        halogens. OH, —O—C₁₋₇-alkyl, —S—C₁₋₆-alkyl, or —CF₃; or each D        is, independently selected from N(R_(h));    -   Rh is selected from the group H, unsubstituted or substituted        C₁₋₇-alkyl, aryl, unsubstituted or substituted        —O—(C₁₋₇-cycloalkyl), —C(O)—C₁₋₁₀-alkyl, —C(O)—C₀₋₁₀-alkyl-aryl,        —C—O—C₀₁₋₁₀-alkyl, —C—O—C₀₋₁₀-alkyl-aryl, —SO₂—C₁₋₁₀-alkyl, or        —SO₂—(C₀₋₁₀-alkylaryl);    -   R₆, R₇. R₈, and R₉ of Formula (VII) are, independently, selected        from the group H, —C₁₋₁₀-alkyl, —C₁₋₁₀-alkoxy,        aryl-C₁₋₁₀-alkoxy, —OH, —O—C₁₋₁₀-alkyl,        —(CH₂)₀₋₆—C₃₋₇-cycloalkyl, —O—(CH₂)₀₋₆-aryl, phenyl,        —(CH₂)₁₋₆-het, —O—(CH₂)₁₋₆-het, —OR₁₃, —C(O)—R₁₃,        —C(O)—N(R₁₃)(R₁₄), —N(R₁₃)(R₁₄), —S—R₁₃, —S(O)—R₁₃, —S(O)₂—R₁₃,        —S(O)₂—NR₁₃R₁₄, or —NR₁₃—S(O)₂—R₁₄; wherein each alkyl,        cycloalkyl, and aryl is unsubstituted or substituted; and any        R₆, R₇, R₈, and R₉ optionally together form a ring system;    -   R₁₃ and R₁₄ of Formula (VII) are independently selected from the        group H, C₁₋₁₀-alkyl, —(CH₂)₀₋₆—C₃₋₇-cycloalkyl,        —(CH₂)₀₋₆—(CH)₀₋₁-aryl)₁₋₂, —C(O)—C₁₋₁₀-alkyl,        —C(O)—(CH₂)₁₋₆—C₃₋₇-cycloalkyl, —C(O)—O—(CH₂)₀₋₆-aryl,        —C(O)—(CH₂)₀₋₆—O-fluorenyl, —C(O)—NH—(CH₂)₀₋₆-aryl,        —C(O)—(CH₂)₀₋₆-aryl, —C(O)—(CH₂)₀₋₆-het, —C(S)—C₁₋₁₀-alkyl,        —C(S)—(CH₂)₁₋₆—C₃₋₇-cycloalkyl, —C(S)—O—(CH₂)₀₋₆-aryl,        —C(S)—(CH₂)₀₋₆—O-fluorenyl, —C(S)—NH—(CH₂)₀₋₆-aryl,        —C(S)—(CH₂)₀₋₆-aryl, or —C(S)—(CH₂)₁₋₆-het, wherein each alkyl,        cycloalkyl, and aryl is unsubstituted or substituted: or any R₁₃        and R₁₄ together with a nitrogen atom form het;    -   wherein alkyl substituents of R₁₃ and R₁₄ of Formula (VII) are        unsubstituted or substituted and when substituted, are        substituted by one or more substituents selected from        C₁₋₁₀-alkyl, halogen, OH, —O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl, and        —CF₃; and substituted phenyl or aryl of R₁₃ and R₁₄ are        substituted by one or more substituents selected from halogen,        hydroxyl. C₁₋₄-alkyl, C₁₋₄-alkoxy, nitro, —CN,        —O—C(O)—C₁₋₄-alkyl, and —C(O)—O—C₁₋₄-aryl; or a pharmaceutically        acceptable salt or hydrate thereof.

In certain embodiments, the compound further comprises an independentlyselected second ILM attached to the ILM of Formula (VI), or an unnaturalmimetic thereof, by way of at least one additional independentlyselected linker group. In an embodiment, the second ILM is a derivativeof Formula (VI), or an unnatural mimetic thereof. In a certainembodiment, the at least one additional independently selected linkergroup comprises two additional independently selected linker groupschemically linking the ILM and the second ILM. In an embodiment, the atleast one additional linker group for an ILM of the Formula (VI), or anunnatural mimetic thereof, chemically links groups selected from R₄ andR₅. For example, an ILM of Formula (VI) and a second ILM of Formula(VI), or an unnatural mimetic thereof, can be linked as shown below:

In certain embodiments, the ILM, the at least one additionalindependently selected linker group L, and the second ILM has astructure selected from the group consisting of:

-   -   which are derivatives of IAP antagonists described in WO Pub.        No. 2008/014236.

In any of the compounds described herein, the ILM can have the structureof Formula (VIII), which is based on the IAP ligands described inNdubaku, C., et al. Antagonism of c-IAP and XIAP proteins is requiredfor efficient induction of cell death by small-molecule IAP antagonists,ACS Chem. Biol., 557-566, 4 (7) (2009), or an unnatural mimetic thereof:

-   -   wherein each of A1 and A2 of Formula (VIII) is independently        selected from optionally substituted monocyclic, fused rings,        aryls and heteroaryls; and    -   R of Formula (VIII) is selected from H or Me.

In a particular embodiment, the linker group L is attached to A1 ofFormula (VIII). In another embodiment, the linker group L is attached toA2 of Formula (VIII).

In a particular embodiment, the ILM is selected from the groupconsisting of

In any of the compounds described herein, the ILM can have the structureof Formula (IX), which is derived from the chemotypes cross-referencedin Mannhold, R., et al. IAP antagonists: promising candidates for cancertherapy, Drug Discov. Today, 15 (5-6), 210-9 (2010), or an unnaturalmimetic thereof:

-   -   wherein R¹ is selected from alkyl, cycloalkyl and        heterocycloalkyl and, most preferably, from isopropyl,        tert-butyl, cyclohexyl and tetrahydropyranyl, and R² of        Formula (IX) is selected from —OPh or H.

In any of the compounds described herein, the ILM can have the structureof Formula (X), which is derived from the chemotypes cross-referenced inMannhold, R., et al. IAP antagonists: promising candidates for cancertherapy, Drug Discov. Today, 15 (5-6), 210-9 (2010), or an unnaturalmimetic thereof:

-   -   wherein:    -   R¹ of Formula (X) is selected from H, —CH₂OH, —CH₂CH₂OH,        —CH₂NH₂, —CH₂CH₂NH₂;    -   X of Formula (X) is selected from S or CH₂;    -   R² of Formula (X) is selected from:

-   -   R³ and R⁴ of Formula (X) are independently selected from H or Me

In any of the compounds described herein, the ILM can have the structureof Formula (XI), which is derived from the chemotypes cross-referencedin Mannhold, R., et al. IAP antagonists: promising candidates for cancertherapy, Drug Discov. Today, 15 (5-6), 210-9 (2010), or an unnaturalmimetic thereof:

-   -   wherein R¹ of Formula (XI) is selected from H or Me, and R² of        Formula (XI) is selected from H or

In any of the compounds described herein, the ILM can have the structureof Formula (XII), which is derived from the chemotypes cross-referencedin Mannhold, R., et al. IAP antagonists: promising candidates for cancertherapy, Drug Discov. Today, 15 (5-6), 210-9 (2010), or an unnaturalmimetic thereof:

-   -   wherein:    -   R¹ of Formula (XII) is selected from:

-   -   and    -   R² of Formula (XII) is selected from:

In any of the compounds described herein, the IAP E3 ubiquitin ligasebinding moiety is selected from the group consisting of:

In any of the compounds described herein, the ILM can have the structureof Formula (XIII), which is based on the IAP ligands summarized inFlygare, J. A., et al. Small-molecule pan-IAP antagonists: a patentreview, Expert Opin. Ther. Pat., 20 (2), 251-67 (2010), or an unnaturalmimetic thereof:

-   -   wherein:        -   Z of Formula (XIII) is absent or 0;        -   R¹ of Formula (XIII) is selected from:

-   -   -   R¹⁰ of

-   -   -    is selected from H, alkyl, or aryl;        -   X is selected from CH2 and O; and

-   -   -    is a nitrogen-containing heteroaryl.

In any of the compounds described herein, the ILM can have the structureof Formula (XIV), which is based on the IAP ligands summarized inFlygare, J. A., et al. Small-molecule pan-IAP antagonists: a patentreview, Expert Opin. Ther. Pat., 20 (2), 251-67 (2010), or an unnaturalmimetic thereof:

wherein:

-   -   Z of Formula (XIV) is absent or 0;    -   R³ and R⁴ of Formula (XIV) are independently selected from H or        Me;    -   R¹ of Formula (XIV) is selected from:

-   -   R¹⁰ of

is selected from H, alkyl, or aryl;

-   -   X of

is selected from CH2 and O; and

is a nitrogen-containing heteraryl.

In any of the compounds described herein, the ILM is selected from thegroup consisting of:

-   -   which are derivatives of ligands disclose in US Patent Pub. No.        2008/0269140 and U.S. Pat. No. 7,244,851.

In any of the compounds described herein, the ILM can have the structureof Formula (XV), which was a derivative of the IAP ligand described inWO Pub. No. 2008/128171, or an unnatural mimetic thereof:

wherein:

-   -   Z of Formula (XV) is absent or 0;    -   R¹ of Formula (XV) is selected from:

-   -   R¹⁰ of

is selected from H, alkyl, or aryl;

-   -   X of

is selected from CH2 and O; and

is a nitrogen-containing heteraryl; and

-   -   R² of Formula (XV) selected from H, alkyl, or acyl;

In a particular embodiment, the ILM has the following structure:

In any of the compounds described herein, the ILM can have the structureof Formula (XVI), which is based on the TAP ligand described in WO Pub.No. 2006/069063, or an unnatural mimetic thereof:

-   -   wherein:    -   R² of Formula (XVI) is selected from alkyl, cycloalkyl and        heterocycloalkyl; more preferably, from isopropyl, tert-butyl,        cyclohexyl and tetrahydropyranyl, most preferably from        cyclohexyl;

of Formula (XVI) is a 5- or 6-membered nitrogen-containing heteroaryl;more preferably, 5-membered nitrogen-containing heteroaryl, and mostpreferably thiazole; and Ar of Formula (XVI) is an aryl or a heteroaryl.

In any of the compounds described herein, the ILM can have the structureof Formula (XVII), which is based on the IAP ligands described in Cohen,F. et al., Antagonists of inhibitors of apoptosis proteins based onthiazole amide isosteres, Bioorg. Med. Chem. Lett., 20(7), 2229-33(2010), or an unnatural mimetic thereof:

-   -   wherein:    -   R¹ of Formula (XVII) is selected from the group halogen (e.g.        fluorine), cyano,

-   -   X of Formula (XVII) is selected from the group O or CH2.

In any of the compounds described herein, the ILM can have the structureof Formula (XVIII), which is based on the IAP ligands described inCohen, F. et al., Antagonists of inhibitors of apoptosis proteins basedon thiazole amide isosteres, Bioorg. Med. Chem. Lett., 20(7), 2229-33(2010), or an unnatural mimetic thereof:

-   -   wherein R of Formula (XVIII) is selected from alkyl, aryl,        heteroaryl, arylalkyl, heteroarylalkyl or halogen (in variable        substitution position).

In any of the compounds described herein, the ILM can have the structureof Formula (XIX), which is based on the IAP ligands described in Cohen,F. et al., Antagonists of inhibitors of apoptosis proteins based onthiazole amide isosteres, Bioorg. Med. Chem. Lett., 20(7), 2229-33(2010), or an unnatural mimetic thereof:

-   -   wherein

is a 6-member nitrogen heteroaryl.

In a certain embodiment, the ILM of the composition is selected from thegroup consisting of:

In certain embodiments, the ILM of the composition is selected from thegroup consisting of:

In any of the compounds described herein, the ILM can have the structureof Formula (XX), which is based on the IAP ligands described in WO Pub.No. 2007/101347, or an unnatural mimetic thereof:

-   -   wherein X of Formula (XX) is selected from CH₂, O, NH, or S.

In any of the compounds described herein, the ILM can have the structureof Formula (XXI), which is based on the IAP ligands described in U.S.Pat. Nos. 7,345,081 and 7,419,975, or an unnatural mimetic thereof:

wherein:

-   -   R² of Formula (XXI) is selected from:

-   -   R⁵ of Formula (XXI) is selected from:

and

-   -   W of Formula (XXI) is selected from CH or N; and    -   R⁶ of

and are independently a mono- or bicyclic fused aryl or heteroaryl.

In certain embodiments, the ILM of the compound is selected from thegroup consisting of:

In certain embodiments, the ILM of the compound is selected from thegroup consisting of:

which are described in WO Pub. No. 2009/060292, U.S. Pat. No. 7,517,906,WO Pub. No. 2008/134679, WO Pub. No. 2007/130626, and WO Pub. No.2008/128121.

In any of the compounds described herein, the ILM can have the structureof Formula (XXII) or (XXIII), which are derived from the IAP ligandsdescribed in WO Pub. No. 2015/006524 and Perez H L, Discovery of potentheterodimeric antagonists of inhibitor of apoptosis proteins (IAPs) withsustained antitumor activity. J. Med. Chem. 58(3), 1556-62 (2015), or anunnatural mimetic thereof:

wherein:

-   -   R¹ of Formula (XXII) or (XXIII) is optionally substituted alkyl,        optionally substituted cycloalkyl, optionally substituted        cycloalkylalkyl, optionally substituted heterocyclyl, optionally        substituted arylalkyl or optionally substituted aryl;    -   R² of Formula (XXII) or (XXIII) is optionally substituted alkyl,        optionally substituted cycloalkyl, optionally substituted        cycloalkylalkyl, optionally substituted heterocyclyl, optionally        substituted arylalkyl or optionally substituted aryl;    -   or alternatively, R¹ and R² of Formula (XXII) or (XXIII) are        independently optionally substituted thioalkyl wherein the        substituents attached to the S atom of the thioalkyl are        optionally substituted alkyl, optionally substituted branched        alkyl, optionally substituted heterocyclyl, —(CH₂)_(v)COR²⁰,        —CH₂CHR²¹COR²² or —CH₂R²³.    -   wherein:    -   v is an integer from 1-3;    -   R²⁰ and R²² of —(CH₂)_(v)COR²⁰ and —CH₂R²³ are independently        selected from OH, NR²⁴R²⁵ or OR²⁶;    -   R²¹ of —CH₂CHR²¹COR² is selected from the group NR²⁴R²⁵.    -   R²³ of —CH₂R²³ is selected from optionally substituted aryl or        optionally substituted heterocyclyl, where the optional        substituents include alkyl and halogen;    -   R²⁴ of NR²⁴R²⁵ is selected from hydrogen or optionally        substituted alkyl;    -   R²⁵ of NR²⁴R²⁵ is selected from hydrogen, optionally substituted        alkyl, optionally substituted branched alkyl, optionally        substituted arylalkyl, optionally substituted heterocyclyl,        —CH₂(OCH₂CH₂O)_(m)CH₃, or a polyamine chain, such as spermine or        spermidine;    -   R²⁶ of OR²⁶ is selected from optionally substituted alkyl,        wherein the optional substituents are OH, halogen or NH₂; and    -   m is an integer from 1-8;    -   R³ and R⁴ of Formula (XXII) or (XXIII) are independently        selected from optionally substituted alkyl, optionally        substituted cycloalkyl, optionally substituted aryl, optionally        substituted arylalkyl, optionally substituted arylalkoxy,        optionally substituted heteroaryl, optionally substituted        heterocyclyl, optionally substituted heteroarylalkyl or        optionally substituted heterocycloalkyl, wherein the        substituents are alkyl, halogen or OH;    -   R⁵, R⁶, R⁷ and R⁸ of Formula (XXII) or (XXIII) are independently        selected from hydrogen, optionally substituted alkyl or        optionally substituted cycloalkyl; and    -   X is selected from a bond or a chemical linker group, and/or a        pharmaceutically acceptable salt, tautomer or stereoisomer        thereof.

In certain embodiments, X is a bond or is selected from the groupconsisting of:

wherein “*” is the point of attachment of a PTM, L or ULM, e.g., an ILM.

In any of the compounds described herein, the ILM can have the structureof Formula (XXIV) or (XXVI), which are derived from the IAP ligandsdescribed in WO Pub. No. 2015/006524 and Perez H L, Discovery of potentheterodimeric antagonists of inhibitor of apoptosis proteins (IAPs) withsustained antitumor activity. J. Med. Chem. 58(3), 1556-62 (2015), or anunnatural mimetic thereof, and the chemical linker to linker group L asshown:

wherein:

-   -   R¹ of Formula (XXIV), (XXV) or (XXVI) is selected from        optionally substituted alkyl, optionally substituted cycloalkyl,        optionally substituted cycloalkylalkyl, optionally substituted        heterocyclyl, optionally substituted arylalkyl or optionally        substituted aryl;    -   R² of Formula (XXIV), (XXV) or (XXVI) is selected from        optionally substituted alkyl, optionally substituted cycloalkyl,        optionally substituted cycloalkylalkyl, optionally substituted        heterocyclyl, optionally substituted arylalkyl or optionally        substituted aryl;    -   or alternatively,    -   R¹ and R² of Formula (XXIV), (XXV) or (XXVI) are independently        selected from optionally substituted thioalkyl wherein the        substituents attached to the S atom of the thioalkyl are        optionally substituted alkyl, optionally substituted branched        alkyl, optionally substituted heterocyclyl, —(CH₂)_(v)COR²⁰,        —CH₂CHR²¹COR²² or —CH₂R²³,    -   wherein:        -   v is an integer from 1-3;        -   R²⁰ and R²² of —(CH₂)_(v)COR²⁰ and —CH₂R²³ are independently            selected from OH, NR²⁴R²⁵ or OR²⁶;        -   R²¹ of —CH₂CHR²¹COR² is selected from NR²⁴R²⁵;        -   R²³ of —CH₂R²³ is selected from optionally substituted aryl            or optionally substituted heterocyclyl, wherein the optional            substituents include alkyl and halogen;        -   R²⁴ of NR²⁴R²⁵ is selected from hydrogen or optionally            substituted alkyl;        -   R²⁵ of NR²⁴R²⁵ is selected from hydrogen, optionally            substituted alkyl, optionally substituted branched alkyl,            optionally substituted arylalkyl, optionally substituted            heterocyclyl, —CH₂(OCH₂CH₂O)_(m)CH₃, or a polyamine chain,            such as spermine or spermidine;        -   R²⁶ of OR²⁶ is selected from optionally substituted alkyl,            wherein the optional substituents are OH, halogen or NH₂;            and        -   m is an integer from 1-8;        -   R³ and R⁴ of Formula (XXIV), (XXV) or (XXVI) are            independently optionally substituted alkyl, optionally            substituted cycloalkyl, optionally substituted aryl,            optionally substituted arylalkyl, optionally substituted            arylalkoxy, optionally substituted heteroaryl, optionally            substituted heterocyclyl, optionally substituted            heteroarylalkyl or optionally substituted heterocycloalkyl,            wherein the substituents are alkyl, halogen or OH;        -   R⁵, R⁶, R⁷ and R⁸ of Formula (XXIV), (XXV) or (XXVI) are            independently hydrogen, optionally substituted alkyl or            optionally substituted cycloalkyl; and/or a pharmaceutically            acceptable salt, tautomer or stereoisomer thereof.

In a particular embodiment, the ILM according to Formulas (XXII) through(XXVI):

-   -   R⁷ and R⁸ are selected from the H or Me;    -   R⁵ and R⁶ are selected from the group comprising:

-   -   R³ and R⁴ are selected from the group comprising:

In any of the compounds described herein, the ILM can have the structureof Formula (XXVII) or (XXVII), which are derived from the IAP ligandsdescribed in WO Pub. No. 2014/055461 and Kim, K S, Discovery oftetrahydroisoquinoline-based bivalent heterodimeric IAP antagonists.Bioorg. Med. Chem. Lett. 24(21), 5022-9 (2014), or an unnatural mimeticthereof:

wherein:

-   -   R³⁵ is 1-2 substituents selected from alkyl, halogen, alkoxy,        cyano and haloalkoxy;    -   R¹ of Formula (XXVII) and (XXVIII) is selected from H or an        optionally substituted alkyl, optionally substituted cycloalkyl,        optionally substituted cycloalkylalkyl, optionally substituted        heterocyclyl, optionally substituted arylalkyl or optionally        substituted aryl;    -   R² of Formula (XXVII) and (XXVIII) is selected from H or an        optionally substituted alkyl, optionally substituted cycloalkyl,        optionally substituted cycloalkylalkyl, optionally substituted        heterocyclyl, optionally substituted arylalkyl or optionally        substituted aryl;    -   or alternatively,    -   R¹ and R² of Formula (XXVII) and (XXVIII) are independently        selected from an optionally substituted thioalkyl —CR⁶⁰R⁶¹SR⁷⁰,        wherein R⁶⁰ and R⁶¹ are selected from H or methyl, and R⁷⁰ is        selected from an optionally substituted alkyl, optionally        substituted branched alkyl, optionally substituted heterocyclyl,        —(CH₂)_(v)COR²⁰, —CH₂CHR²¹COR²² or —CH₂R²³,    -   wherein:        -   v is an integer from 1-3;        -   R²⁰ and R²² of —(CH₂)_(v)COR²⁰ and —CH₂CHR²¹COR²² are            independently selected from OH, NR²⁴R²⁵ or OR²⁶;        -   R²¹ of —CH₂CHR²¹COR²² is selected from NR²⁴R²⁵;        -   R²³ of —CH₂R²³ is selected from an optionally substituted            aryl or optionally substituted heterocyclyl, where the            optional substituents include alkyl and halogen;        -   R²⁴ of NR²⁴R²⁵ is selected from hydrogen or optionally            substituted alkyl;        -   R²⁵ of NR²⁴R²⁵ is selected from hydrogen, optionally            substituted alkyl, optionally substituted branched alkyl,            optionally substituted arylalkyl, optionally substituted            heterocyclyl, —CH₂CH₂(OCH₂CH₂)_(m)CH₃, or a polyamine chain            —[CH₂CH₂(CH₂)_(δ)NH]_(ψ)CH₂CH₂(CH₂)ωNH₂, such as spermine or            spermidine;        -   wherein δ=0-2, ψ=1-3, ω=0-2;        -   R²⁶ of OR²⁶ is an optionally substituted alkyl, wherein the            optional substituents are OH, halogen or NH₂; and        -   m is an integer from 1-8,        -   R³ and R⁴ of Formula (XXVII) and (XXVIII) are independently            selected from an optionally substituted alkyl, optionally            substituted cycloalkyl, optionally substituted aryl,            optionally substituted arylalkyl, optionally substituted            arylalkoxy, optionally substituted heteroaryl, optionally            substituted heterocyclyl, optionally substituted            heteroarylalkyl or optionally substituted heterocycloalkyl,            wherein the substituents are alkyl, halogen or OH;        -   R⁵, R⁶, R⁷ and R⁸ of Formula (XXVII) and (XXVIII) are            independently selected from hydrogen, optionally substituted            alkyl or optionally substituted cycloalkyl;        -   R³¹ of Formulas (XXVII) and (XXVIII) is selected from alkyl,            aryl, arylalkyl, heteroaryl or heteroarylalkyl optionally            further substituted, preferably selected form the group            consisting of:

-   -   -   X of Formulas (XXVII) and (XXVIII) is selected from            —(CR⁸¹R⁸²)_(m)—, optionally substituted heteroaryl or            heterocyclyl,

-   -   -   Z of Formulas (XXVII) is selected from C═O, —O—, —NR,            —CONH—, —NHCO—, or may be absent;        -   R⁸¹ and R⁸² of —(CR⁸¹R⁸²)_(m)— are independently selected            from hydrogen, halogen, alkyl or cycloalkyl, or R⁸¹ and R⁸²            can be taken together to form a carbocyclic ring;        -   R¹⁰ and R¹¹ of

-   -   -    are independently selected from hydrogen, halogen or alkyl;        -   R¹², R¹³, R¹⁴, R¹⁵ and R¹⁶ of

-   -   -    are independently selected from hydrogen, halogen or            optionally substituted alkyl or OR¹⁷;        -   R¹⁷ is selected from hydrogen, optionally substituted alkyl            or optionally substituted cycloalkyl;        -   m and n of —(CR²¹R²²)_(m)— and

-   -   -    are independently 0, 1, 2, 3, or 4;        -   and p of

-   -   -    are independently 0, 1, 2 or 3;        -   q and t of

-   -   -    are independently 0, 1, 2, 3, or 4;        -   r of

-   -   -    is 0 or 1;

    -   and/or a pharmaceutically acceptable salt, tautomer or        stereoisomer thereof.

In any of the compounds described herein, the ILM can have the structureof Formula (XXIX), (XXX), (XXXI), or (XXXII), which are derived from theIAP ligands described in WO Pub. No. 2014/055461 and Kim, K S, Discoveryof tetrahydroisoquinoline-based bivalent heterodimeric IAP antagonists.Bioorg. Med. Chem. Lett. 24(21), 5022-9 (2014), or an unnatural mimeticthereof, and the chemical linker to linker group L as shown:

wherein:

-   -   R² of Formula (XXIX) through (XXXII) is selected from H, an        optionally substituted alkyl, optionally substituted cycloalkyl,        optionally substituted cycloalkylalkyl, optionally substituted        heterocyclyl, optionally substituted arylalkyl or optionally        substituted aryl;    -   or alternatively;    -   R¹ and R² of Formula (XXVII) and (XXVIII) are independently        selected from H, an optionally substituted thioalkyl        —CR⁶⁰R⁶¹SR⁷⁰ wherein R⁶⁰ and R⁶¹ are selected from H or methyl,        and R⁷⁰ is an optionally substituted alkyl, optionally        substituted branched alkyl, optionally substituted heterocyclyl,        —(CH₂)_(v)COR²⁰, —CH₂CHR²¹COR²² or —CH₂R²³.    -   wherein:    -   v is an integer from 1-3;    -   R²⁰ and R²² of —(CH₂)_(v)COR²⁰ and —CH₂CHR²¹COR²² are        independently selected from OH, NR²⁴R²⁵ or OR²⁶.    -   R²¹ of —CH₂CHR²¹COR²² is selected from NR²⁴R²⁵.    -   R²³ of —CH₂R²³ is selected from an optionally substituted aryl        or optionally substituted heterocyclyl, where the optional        substituents include alkyl and halogen;    -   R²⁴ of NR²⁴R²⁵ is selected from hydrogen or optionally        substituted alkyl;    -   R²⁵ of NR²⁴R²⁵ is selected from hydrogen, optionally substituted        alkyl, optionally substituted branched alkyl, optionally        substituted arylalkyl, optionally substituted heterocyclyl,        —CH₂CH₂(OCH₂CH₂)_(m)CH₃, or a polyamine chain        —[CH₂CH₂(CH₂)₈NH]_(ψ)CH₂CH₂(CH₂){dot over (ψ)}_(r)NH₂, such as        spermine or spermidine,    -   wherein δ=0-2, ψ=1-3, {dot over (ω)}=0-2;    -   R²⁶ of OR²⁶ is an optionally substituted alkyl, wherein the        optional substituents are OH, halogen or NH₂;    -   m is an integer from 1-8;    -   R⁶ and R⁸ of Formula (XXIX) through (XXXII) are independently        selected from hydrogen, optionally substituted alkyl or        optionally substituted cycloalkyl; and    -   R³¹ of Formulas (XXIX) through (XXXII) is selected from alkyl,        aryl, arylalkyl, heteroaryl or heteroarylalkyl optionally        further substituted, preferably selected form the group        consisting of:

In certain embodiments, the ILM of the compound is:

In any of the compounds described herein, the ILM can have the structureof Formula (XXXIII), which are derived from the IAP ligands described inWO Pub. No. 2014/074658 and WO Pub. No. 2013/071035, or an unnaturalmimetic thereof:

wherein:

-   -   R² of Formula (XXXIII) is selected from H, an optionally        substituted alkyl, optionally substituted cycloalkyl, optionally        substituted cycloalkylalkyl, optionally substituted        heterocyclyl, optionally substituted arylalkyl or optionally        substituted aryl;    -   R⁶ and R⁸ of Formula (XXXIII) are independently selected from        hydrogen, optionally substituted alkyl or optionally substituted        cycloalkyl;    -   R³² of Formula (XXXIII) is selected from (C1-C4 alkylene)-R³³        wherein R³³ is selected from hydrogen, aryl, heteroaryl or        cycloalkyl optionally further substituted;    -   X of Formula (XXXIII) is selected from:

-   -   Z and Z′ of Formula (XXXIII) are independently selected from:

wherein each

represents a point of attachment to the compound, and Z and Z′

-   -   cannot both be

in any given compound;

-   -   Y of Formula (XXXIII) is selected from:

wherein Z and Z′ of Formula (XXXIII) are the same and Z is

wherein each

represents a point of attachment to the compound, X is selected from:

and

-   -   Y of Formula (XXXIII) is independently selected from:

wherein:

represents a point of attachment to a —C═O portion of the compound;

represents a point of attachment to a —NH portion of the compound;

represents a first point of attachment to Z;

represents a second point of attachment to Z;

-   -   m is an integer from 0-3;    -   n is an integer from 1-3;    -   p is an integer from 0-4; and    -   A is —C(O)R³;    -   R³ is selected from —C(O)R³ is OH, NHCN, NHSO₂R¹⁰, NHOR¹¹ or        N(R¹²)(R¹³);    -   R¹⁰ and F¹¹ of NHSO₂R¹⁰ and NHOR¹¹ are independently selected        from hydrogen, optionally substituted —C₁-C₄ alkyl, cycloalkyl,        aryl, heteroaryl, heterocyclyl or heterocycloalkyl;    -   R¹² and R¹³ of N(R¹²)(R¹³) are independently selected from        hydrogen, —C₁-C₄ alkyl, —(C₁-C₄) alkylene)-NH—(C₁-C₄ alkyl), and        —(C₁-C₄ alkylene)-O—(C₁-C₄ hydroxyalkyl), or R¹² and R¹³ taken        together with the nitrogen atom to which they are commonly bound        to form a saturated heterocyclyl optionally comprising one        additional heteroatom selected from N, O and S, and wherein the        saturated heterocycle is optionally substituted with methyl.

In any of the compounds described herein, the ILM can have the structureof Formula (XXXIV) or (XXXV), which are derived from the IAP ligandsdescribed in WO Pub. No. 2014/047024, or an unnatural mimetic thereof:

wherein:

-   -   X of Formula (XXXIV) or (XXXV) is absent or a group selected        from —(CR¹⁰R¹¹)_(m), optionally substituted heteroaryl or        optionally substituted heterocyclyl,

-   -   Y and Z of Formula (XXXIV) or (XXXV) are independently selected        from C═O, —O—, —NR⁹—, —CONH—, —NHCO— or may be absent;    -   R¹ and R² of Formula (XXXIV) or (XXXV) are independently        selected from an optionally substituted alkyl, optionally        substituted cycloalkyl, optionally substituted cycloalkylalkyl,        optionally substituted arylalkyl, optionally substituted aryl,        or    -   R¹ and R² of Formula (XXXIV) or (XXXV) are independently        selected from optionally substituted thioalkyl wherein the        substituents attached to the S atom of the thioalkyl are        optionally substituted alkyl, optionally substituted branched        alkyl, optionally substituted heterocyclyl, —(CH₂)_(v)COR²⁰,        —CH₂CHR²¹COR²² or —CH₂R²³; wherein        -   v is an integer from 1-3;        -   R²⁰ and R²² of —(CH₂)_(v)COR²⁰ and —CH₂CHR²¹COR²² are            independently selected from OH, NR²⁴R²⁵ or OR²⁶;        -   R²¹ of —CH₂CHR²¹COR²² is selected from NR²⁴R²⁵;        -   R²³ of —CH₂R²³ are selected from an optionally substituted            aryl or optionally substituted heterocyclyl, where the            optional substituents include alkyl and halogen;        -   R²⁴ of NR²⁴R²⁵ is selected from hydrogen or optionally            substituted alkyl;        -   R²⁵ of NR²⁴R²⁵ is selected from hydrogen, optionally            substituted alkyl, optionally substituted branched alkyl,            optionally substituted arylalkyl, optionally substituted            heterocyclyl, —CH₂(OCH₂CH²⁰)_(m)CH₃, or a polyamine chain;        -   R²⁶ is an optionally substituted alkyl, wherein the optional            substituents are OH, halogen or NH₂;        -   m of —(CR¹⁰R¹¹)_(m) is an integer from 1-8;    -   R³ and R⁴ of Formula (XXXIV) or (XXXV) are independently        selected from optionally substituted alkyl, optionally        substituted cycloalkyl, optionally substituted aryl, optionally        substituted arylalkyl, optionally substituted arylalkoxy,        optionally substituted heteroaryl, optionally substituted        heterocyclyl, optionally substituted heteroarylalkyl or        optionally substituted heterocycloalkyl, wherein the        substituents are alkyl, halogen or OH;    -   R⁵, R⁶, R⁷ and R⁸ of Formula (XXXIV) or (XXXV) are independently        selected from hydrogen, optionally substituted alkyl or        optionally substituted cycloalkyl;    -   R¹⁰ and R¹¹ of —(CR¹⁰R¹¹)_(m) are independently selected from        hydrogen, halogen or optionally substituted alkyl;    -   R¹² and R¹³ of

are independently selected from hydrogen, halogen or optionallysubstituted alkyl, or R¹² and R¹³ can be taken together to form acarbocyclic ring;

-   -   R¹⁴, R¹⁵, R¹⁶, R¹⁷ and R¹⁸ of

are independently selected from hydrogen, halogen, optionallysubstituted alkyl or OR¹⁹;

-   -   R¹⁹ of OR¹⁹ is selected from hydrogen, optionally substituted        alkyl or optionally substituted cycloalkyl;    -   m and n of —(CR¹⁰R¹¹)_(m)— are independently 0, 1, 2, 3, or 4;    -   o and p of —(CR¹⁰R¹¹)_(m)— are independently 0, 1, 2 or 3;    -   q of —(CR¹⁰R¹¹)_(m)— is 0, 1, 2, 3, or 4; r is 0 or 1;    -   t of —(CR¹⁰R¹¹)_(m)— is 1, 2, or 3; and/or a pharmaceutically        acceptable salt, tautomer or stereoisomer thereof.

In any of the compounds described herein, the ILM can have the structureof Formula (XXXVI), which are derived from the IAP ligands described inWO Pub. No. 2014/025759, or an unnatural mimetic thereof:

where:

-   -   A of Formula (XXXVI) is selected from:

where the dotted line represents an optional double bond;

-   -   X of Formula (XXXVI) is selected from: —(CR²¹R²²)_(m)—,

-   -   Y and Z of Formula (XXXVI) are independently selected from —O—,        —NR⁶— or are absent;    -   V of Formula (XXXVI) is selected from —N— or —CH—;    -   W of Formula (XXXVI) is selected from —CH— or —N—;    -   R¹ of Formula (XXXVI) is selected from an optionally substituted        alkyl, optionally substituted cycloalkyl, optionally substituted        cycloalkylalkyl, optionally substituted arylalkyl or optionally        substituted aryl;    -   R³ and R⁴ of Formula (XXXVI) are independently selected from        optionally substituted alkyl, optionally substituted cycloalkyl,        optionally substituted aryl, optionally substituted heteroaryl,        optionally substituted heterocyclyl, optionally substituted        arylalkyl, optionally substituted heteroarylalkyl or optionally        substituted heterocycloalkyl;    -   R⁵, R⁶, R⁷ and R⁸ of Formula (XXIV), (XXV) or (XXVI) are        independently selected from hydrogen, optionally substituted        alkyl or optionally substituted cycloalkyl, or preferably        methyl;    -   R⁹ and R¹⁰ of

are independently selected from hydrogen, halogen or optionallysubstituted alkyl, or R⁹ and R¹⁰ can be taken together to form a ring;

-   -   R¹¹, R¹², R¹³ and R¹⁴ of

are independently selected from hydrogen, halogen, optionallysubstituted alkyl or OR¹⁵;

-   -   R¹⁵ of OR¹⁵ is selected from hydrogen, optionally substituted        alkyl or optionally substituted cycloalkyl;    -   m and n of —(CR²¹R²²)_(m)— and

are independently selected from 0, 1, 2, 3, or 4;

-   -   and p of

and are independently selected from 0, 1, 2 or 3;

-   -   q of

is selected from 0, 1, 2, 3, or 4;

-   -   r of

is selected from 0 or 1, and/or or a pharmaceutically acceptable salt,tautomer or stereoisomer thereof.

In any of the compounds described herein, the ILM can have the structureof Formula (XXXVII) or (XXXVIII), which are derived from the IAP ligandsdescribed in WO Pub. No. 2014/011712, or an unnatural mimetic thereof:

wherein:

-   -   X of Formulas (XXXVII) and (XXXVIII) is —(CR¹⁶R¹⁷)_(m)—,

-   -   -   or absent;

    -   Y and Z of Formula (XXXVII) and (XXXVIII) are independently        selected from —O—, C═O, NR⁶ or are absent;

    -   R¹ and R² of Formula (XXXVII) and (XXXVIII) are selected from        optionally substituted alkyl, optionally substituted cycloalkyl,        optionally substituted alkylaryl or optionally substituted aryl;

    -   R³ and R⁴ of Formula (XXXVII) and (XXXVIII) are independently        selected from optionally substituted alkyl, optionally        substituted cycloalkyl, optionally substituted cycloalkylalkyl,        optionally substituted arylalkyl or optionally substituted aryl;

    -   R⁵ and R⁶ of Formula (XXXVII) and (XXXVIII) are independently        selected from optionally substituted alkyl or optionally        substituted cycloalkyl;

    -   R⁷ and R⁸ of Formula (XXXVII) and (XXXVIII) are independently        selected from hydrogen, optionally substituted alkyl or        optionally substituted cycloalkyl, or preferably methyl;

    -   R⁹ and R¹⁰ of

are independently selected from hydrogen, optionally substituted alkyl,or R⁹ and R¹⁰ may be taken together to form a ring;

-   -   R¹¹ to R¹⁴ of

are independently selected from hydrogen, halogen, optionallysubstituted alkyl or OR¹⁵;

-   -   R¹⁵ of OR¹⁵ is selected from hydrogen, optionally substituted        alkyl or optionally substituted cycloalkyl;    -   R¹⁶ and R¹⁷ of —(CR¹⁶R¹⁷)_(m)— are independently selected from        hydrogen, halogen or optionally substituted alkyl;    -   R⁵⁰ and R⁵¹ of Formula (XXXVII) and (XXXVIII) are independently        selected from optionally substituted alkyl, or R⁵⁰ and R⁵¹ are        taken together to form a ring;    -   m and n of —(CR¹⁶R¹⁷)_(m)— and

are independently an integer from 0-4;

-   -   o and p of

are independently an integer from 0-3;

-   -   q of

is an integer from 0-4; and

-   -   r of

is an integer from 0-1;

-   -   or a pharmaceutically acceptable salt, tautomer or stereoisomer        thereof.

In an embodiment, R¹ and R² of the ILM of Formula (XXXVII) or (XXXVIII)are t-butyl and R³ and R⁴ of the ILM of Formula (XXXVII) or (XXXVIII)are tetrahydronaphtalene.

In any of the compounds described herein, the ILM can have the structureof Formula (XXXIX) or (XL), which are derived from the IAP ligandsdescribed in WO Pub. No. 2013/071039, or an unnatural mimetic thereof:

wherein:

-   -   R⁴³ and R⁴⁴ of Formulas (XXXIX) and (XL) are independently        selected from hydrogen, alkyl, aryl, arylalkyl, heteroaryl,        heteroarylalkyl, cycloalkyl, cycloalkylalkyl further optionally        substituted, and    -   R⁶ and R⁸ of Formula (XXXIX) and (XL) are independently selected        from hydrogen, optionally substituted alkyl or optionally        substituted cycloalkyl.    -   each X of Formulas (XXXIX) and (XL) is independently selected        from:

-   -   each Z of Formulas (XXXIX) and (XL) is selected from

wherein each

represents a point of attachment to the compound; and

-   -   each Y is selected from:

wherein:

represents a point of attachment to a —C═O portion of the compound;

represents a point of attachment to an amino portion of the compound;

represents a first point of attachment to Z;

represents a second point of attachment to Z; andA is selected from —C(O)R³ or

or a tautomeric form of any of the foregoing, wherein:

-   -   R³ of —C(O)R³ is selected from OH, NHCN, NHSO₂R¹⁰, NHOR¹¹ or        N(R¹²)(R³);    -   R¹⁰ and R¹¹ of NHSO₂R¹⁰ and NHOR¹¹ are independently selected        from —C₁-C₄ alkyl, cycloalkyl, aryl, heteroaryl, or        heterocycloalkyl, any of which are optionally substituted, and        hydrogen;    -   each of R¹² and R¹³ of N(R¹²)(R¹³) are independently selected        from hydrogen, —C₁-C₄ alkyl, —(C₁-C₄ alkylene)-NH—(C₁-C₄ alkyl),        benzyl, —(C₁-C₄ alkylene)-C(O)OH, —(C₁-C₄ alkylene)-C(O)CH₃,        —CH(benzyl)-COOH, —C₁-C₄ alkoxy, and —(C₁-C₄ alkylene)-O—(C₁-C₄        hydroxyalkyl); or R¹² and R¹³ of N(R¹²)(R¹³) are taken together        with the nitrogen atom to which they are commonly bound to form        a saturated heterocyclyl optionally comprising one additional        heteroatom selected from N, O and S, and wherein the saturated        heterocycle is optionally substituted with methyl.

In any of the compounds described herein, the ILM can have the structureof Formula (XLI), which are derived from the IAP ligands described in WOPub. No. 2013/071039, or an unnatural mimetic thereof:

wherein:

-   -   W¹ of Formula (XLI) is selected from O, S, N—R^(A), or        C(R^(8a))(R^(8b));    -   W² of Formula (XLI) is selected from O, S, N—R^(A), or        C(R^(8c))(R^(8d)); provided that W¹ and W² are not both O, or        both S;    -   R¹ of Formula (XLI) is selected from H, C₁-C₆alkyl,        C₃-C₆cycloalkyl, —C₁-C₆alkyl-(substituted or unsubstituted        C₃-C₆cycloalkyl), substituted or unsubstituted aryl, substituted        or unsubstituted heteroaryl, —C₁-C₆alkyl-(substituted or        unsubstituted aryl), or —C₁-C₆alkyl-(substituted or        unsubstituted heteroaryl);    -   when X¹ is selected from O, N—R^(A), S, S(O), or S(O)₂, then X²        is C(R^(2a)R^(2b));    -   or:    -   X¹ of Formula (XLI) is selected from CR^(2c)R^(2d) and X² is        CR^(2a)R^(2b), and R^(2c) and R^(2a) together form a bond;    -   or:    -   X¹ and X² of Formula (XLI) are independently selected from C and        N, and are members of a fused substituted or unsubstituted        saturated or partially saturated 3-10 membered cycloalkyl ring,        a fused substituted or unsubstituted saturated or partially        saturated 3-10 membered heterocycloalkyl ring, a fused        substituted or unsubstituted 5-10 membered aryl ring, or a fused        substituted or unsubstituted 5-10 membered heteroaryl ring;    -   or:    -   X¹ of Formula (XLI) is selected from CH₂ and X² is C═O,        C═C(R^(C))₂, or C═NR^(C); where each R^(c) is independently        selected from H, —CN, —OH, alkoxy, substituted or unsubstituted        C₁-C₆alkyl, substituted or unsubstituted C₃-C₆cycloalkyl,        substituted or unsubstituted C₂-C₅heterocycloalkyl, substituted        or unsubstituted aryl, substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), or —C₁-C₆alkyl-(substituted or        unsubstituted heteroaryl);    -   R^(A) of N—R^(A) is selected from H, C₁-C₆alkyl,        —C(═O)C₁-C₂alkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R^(2a), R^(2b), R^(2c), R^(2d) of CR^(2c)R^(2d) and        CR^(2a)R^(2b) are independently selected from H, substituted or        unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₁-C₆heteroalkyl, substituted or unsubstituted C₃-C₆cycloalkyl,        substituted or unsubstituted C₂-C₅heterocycloalkyl, substituted        or unsubstituted aryl, substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), —C₁-C₆alkyl-(substituted or unsubstituted        heteroaryl) and —C(═O)R^(B);    -   R^(B) of —C(═O)R^(B) is selected from substituted or        unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₃-C₆cycloalkyl, substituted or unsubstituted        C₂-C₅heterocycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), —C₁-C₆alkyl-(substituted or unsubstituted        heteroaryl), or —NR^(D)R^(E);    -   R^(D) and R^(E) of NR^(D)R^(E) are independently selected from        H, substituted or unsubstituted C₁-C₆alkyl, substituted or        unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted        C₂-C₅heterocycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), or —C₁-C₆alkyl-(substituted or        unsubstituted heteroaryl);    -   m of Formula (XLI) is selected from 0, 1 or 2;    -   —U— of Formula (XLI) is selected from —NHC(═O)—, —C(═O)NH—,        —NHS(═O)₂—, —S(═O)₂NH—, —NHC(═O)NH—, —NH(C═O)O—, —O(C═O)NH—, or        —NHS(═O)₂NH—;    -   R³ of Formula (XLI) is selected from C₁-C₃alkyl, or        C₁-C₃fluoroalkyl;    -   R⁴ of Formula (XLI) is selected from —NHR⁵, —N(R⁵)2, —N+(R⁵)3 or        —OR⁵; each R⁵ of —NHR⁵, —N(R⁵)2, —N+(R⁵)3 and —OR⁵ is        independently selected from H, C₁-C₃alkyl, C₁-C₃haloalkyl,        C₁-C₃heteroalkyl and —C₁-C₃alkyl-(C₃-C₅cycloalkyl);    -   or:    -   R³ and R⁵ of Formula (XLI) together with the atoms to which they        are attached form a substituted or unsubstituted 5-7 membered        ring;    -   or:    -   R³ of Formula (XLI) is bonded to a nitrogen atom of U to form a        substituted or unsubstituted 5-7 membered ring;    -   R⁶ of Formula (XLI) is selected from —NHC(═O)R⁷, —C(═O)NHR⁷,        —NHS(═O)2R⁷, —S(═O)₂NHR⁷; —NHC(═O)NHR⁷, —NHS(═O)₂NHR⁷,        —(C₁-C₃alkyl)-NHC(═O)R⁷, —(C₁-C₃alkyl)-C(═O)NHR⁷,        —(C₁-C₃alkyl)-NHS(═O)2R⁷, —(C₁-C₃alkyl)-S(═O)₂NHR⁷;        —(C₁-C₃alkyl)-NHC(═O)NHR⁷, —(C₁-C₃alkyl)-NHS(═O)2NHR⁷,        substituted or unsubstituted C₂-C₁₀heterocycloalkyl, or        substituted or unsubstituted heteroaryl;    -   each R⁷ of —NHC(═O)R⁷, —C(═O)NHR⁷, —NHS(═O)2R⁷, —S(═O)₂NHR⁷;        —NHC(═O)NHR⁷, —NHS(═O)₂NHR⁷, —(C₁-C₃alkyl)-NHC(═O)R⁷,        —(C₁-C₃alkyl)-C(═O)NHR⁷, —(C₁-C₃alkyl)-NHS(═O)2R⁷,        —(C₁-C₃alkyl)-S(═O)2NHR⁷; —(C₁-C₃alkyl)-NHC(═O)NHR⁷,        —(C₁-C₃alkyl)-NHS(═O)2NHR⁷ is independently selected from        C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆heteroalkyl, a substituted or        unsubstituted C₃-C₁₀cycloalkyl, a substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, a substituted or unsubstituted aryl, a        substituted or unsubstituted heteroaryl, i-C₆alkyl-(substituted        or unsubstituted C₃-C₁₀cycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted C₂-C₁₀heterocycloalkyl, —C₁-C₆alkyl-(substituted        or unsubstituted aryl), —C₁-C₆alkyl-(substituted or        unsubstituted heteroaryl), —(CH₂)p-CH(substituted or        unsubstituted aryl)2, —(CH₂)p-CH(substituted or unsubstituted        heteroaryl)2, —(CH₂)_(P)—CH(substituted or unsubstituted        aryl)(substituted or unsubstituted heteroaryl), -(substituted or        unsubstituted aryl)-(substituted or unsubstituted aryl),        -(substituted or unsubstituted aryl)-(substituted or        unsubstituted heteroaryl), -(substituted or unsubstituted        heteroaryl)-(substituted or unsubstituted aryl), or        -(substituted or unsubstituted heteroaryl)-(substituted or        unsubstituted heteroaryl);    -   p of R⁷ is selected from 0, 1 or 2;    -   R^(8a), R^(8b), R^(8c), and R^(8d) of C(R^(8a))(R^(8b)) and        C(R^(8c))(R^(8d)) are independently selected from H, C₁-C₆alkyl,        C₁-C₆fluoroalkyl, C₁-C₆ alkoxy, C₁-C₆heteroalkyl, and        substituted or unsubstituted aryl;    -   or:    -   R^(8a) and R^(8d) are as defined above, and R^(8b) and R^(8c)        together form a bond;    -   or:    -   R^(8a) and R^(8d) are as defined above, and R^(8b) and R^(8c)        together with the atoms to which they are attached form a        substituted or unsubstituted fused 5-7 membered saturated, or        partially saturated carbocyclic ring or heterocyclic ring        comprising 1-3 heteroatoms selected from S, O and N, a        substituted or unsubstituted fused 5-10 membered aryl ring, or a        substituted or unsubstituted fused 5-10 membered heteroaryl ring        comprising 1-3 heteroatoms selected from S, O and N;    -   or:    -   R^(8c) and R^(8d) are as defined above, and R^(8a) and R^(8b)        together with the atoms to which they are attached form a        substituted or unsubstituted saturated, or partially saturated        3-7 membered spirocycle or heterospirocycle comprising 1-3        heteroatoms selected from S, O and N;    -   or:    -   R^(8a) and R^(8b) are as defined above, and R^(8c) and R^(8d)        together with the atoms to which they are attached form a        substituted or unsubstituted saturated, or partially saturated        3-7 membered spirocycle or heterospirocycle comprising 1-3        heteroatoms selected from S, O and N;    -   where each substituted alkyl, heteroalkyl, fused ring,        spirocycle, heterospirocycle, cycloalkyl, heterocycloalkyl, aryl        or heteroaryl is substituted with 1-3 R⁹; and    -   each R⁹ of R^(8a), R^(8b), R^(8c) and R^(8d) is independently        selected from halogen, —OH, —SH, (C═O), CN, C₁-C₄alkyl,        C₁-C₄fluoroalkyl, C₁-C₄ alkoxy, C₁-C₄ fluoroalkoxy, —NH₂,        —NH(C₁-C₄alkyl), —NH(C₁-C₄alkyl)2, —C(═O)OH, —C(═O)NH₂,        —C(═O)C₁-C₃alkyl, —S(═O)₂CH₃, —NH(C₁-C₄alkyl)-OH,        —NH(C₁-C₄alkyl)-O—(C₁-C₄alkyl), —O(C₁-C₄alkyl)-NH₂;        —O(C₁-C₄alkyl)-NH—(C₁-C₄alkyl), and        —O(C₁-C₄alkyl)-N—(C₁-C₄alkyl)₂, or two R⁹ together with the        atoms to which they are attached form a methylene dioxy or        ethylene dioxy ring substituted or unsubstituted with halogen,        —OH, or C₁-C₃alkyl.

In any of the compounds described herein, the ILM can have the structureof Formula (XLII), which are derived from the IAP ligands described inWO Pub. No. 2013/071039, or an unnatural mimetic thereof:

wherein:

-   -   W¹ of Formula (XLII) is O, S, N—R^(A), or C(R^(8a))(R^(8b));    -   W² of Formula (XLII) is O, S, N—R^(A), or C(R^(8c))(R^(8d));        provided that W¹ and W² are not both O, or both S;    -   R¹ of Formula (XLII) is selected from H, C₁-C₆alkyl,        C₃-C₆cycloalkyl, —C₁-C₆alkyl-(substituted or unsubstituted        C₃-C₆cycloalkyl), substituted or unsubstituted aryl, substituted        or unsubstituted heteroaryl, —C₁-C₆alkyl-(substituted or        unsubstituted aryl), or —C₁-C₆alkyl-(substituted or        unsubstituted heteroaryl); when X¹ of Formula (XLII) is N—R^(A),        then X² is C═O, or CR^(2c)R^(2d), and X³ is CR^(2a)R^(2b);    -   or:    -   when X¹ of Formula (XLII) is selected from S, S(O), or S(O)₂,        then X² is CR^(2c)R^(2d), and X³ is CR^(2a)R^(2b).    -   or:    -   when X¹ of Formula (XLII) is O, then X² is CR^(2c)R^(2d) and        N—R^(A) and X³ is CR^(2a)R^(2b); or:    -   when X¹ of Formula (XLII) is CH₃, then X² is selected from O,        N—R^(A), S, S(O), or S(O)₂, and X³ is CR^(2a)R^(2b);    -   when X¹ of Formula (XLII) is CR^(2e)R^(2f) and X² is        CR^(2c)R^(2d), and R^(2e) and R^(2c) together form a bond, and        X³ of Formula (VLII) is CR^(2a)R^(2b);    -   or:    -   X¹ and X³ of Formula (XLII) are both CH₂ and X² of        Formula (XLII) is C═O, C═C(R^(C))₂, or C═NR^(C); where each        R^(C) is independently selected from H, —CN, —OH, alkoxy,        substituted or unsubstituted C₁-C₆alkyl, substituted or        unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted        C₂-C₅heterocycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), or —C₁-C₆alkyl-(substituted or        unsubstituted heteroaryl);    -   or:    -   X¹ and X² of Formula (XLII) are independently selected from C        and N, and are members of a fused substituted or unsubstituted        saturated or partially saturated 3-10 membered cycloalkyl ring,        a fused substituted or unsubstituted saturated or partially        saturated 3-10 membered heterocycloalkyl ring, a fused        substituted or unsubstituted 5-10 membered aryl ring, or a fused        substituted or unsubstituted 5-10 membered heteroaryl ring, and        X³ is CR^(2a)R^(2b).    -   or:    -   X² and X³ of Formula (XLII) are independently selected from C        and N, and are members of a fused substituted or unsubstituted        saturated or partially saturated 3-10 membered cycloalkyl ring,        a fused substituted or unsubstituted saturated or partially        saturated 3-10 membered heterocycloalkyl ring, a fused        substituted or unsubstituted 5-10 membered aryl ring, or a fused        substituted or unsubstituted 5-10 membered heteroaryl ring, and        X¹ of Formula (VLII) is CR^(2e)R^(2f);    -   R^(A) of N—R^(A) is selected from H, C₁-C₆alkyl,        —C(═O)C₁-C₂alkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R^(2a), R^(2b), R^(2c), R^(2d), R^(2e), and R^(2f) of        CR^(2c)R^(2d), CR^(2a)R^(2b) and CR^(2e)R^(2f) are independently        selected from H, substituted or unsubstituted C₁-C₆alkyl,        substituted or unsubstituted C₁-C₆heteroalkyl, substituted or        unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted        C₂-C₅heterocycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), —C₁-C₆alkyl-(substituted or unsubstituted        heteroaryl) and —C(═O)R^(B);    -   R^(B) of —C(═O)R^(B) is selected from substituted or        unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₃-C₆cycloalkyl, substituted or unsubstituted        C₂-C₅heterocycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), —C₁-C₆alkyl-(substituted or unsubstituted        heteroaryl), or —NR^(D)R^(E);    -   R^(D) and R^(E) of NR^(D)R^(E) are independently selected from        H, substituted or unsubstituted C₁-C₆alkyl, substituted or        unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted        C₂-C₅heterocycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), or —C₁-C₆alkyl-(substituted or        unsubstituted heteroaryl);    -   m of Formula (XLII) is selected from 0, 1 or 2;    -   —U— of Formula (XLII) is selected from —NHC(═O)—, —C(═O)NH—,        —NHS(═O)₂—, —S(═O)₂NH—, —NHC(═O)NH—, —NH(C═O)O—, —O(C═O)NH—, or        —NHS(═O)₂NH—;    -   R³ of Formula (XLII) is selected from C₁-C₃alkyl, or        C₁-C₃fluoroalkyl;    -   R⁴ of Formula (XLII) is selected from —NHR⁵, —N(R⁵)₂, —N+(R⁵)₃        or —OR⁵;    -   each R⁵ of —NHR⁵, —N(R⁵)₂, —N+(R⁵)₃ and —OR⁵ is independently        selected from H, C₁-C₃alkyl, C₁-C₃haloalkyl, C₁-C₃heteroalkyl        and —C₁-C₃alkyl-(C₃-C₅cycloalkyl);    -   or:    -   R³ and R⁵ of Formula (XLII) together with the atoms to which        they are attached form a substituted or unsubstituted 5-7        membered ring;    -   or:    -   R³ of Formula (XLII) is bonded to a nitrogen atom of U to form a        substituted or unsubstituted 5-7 membered ring;    -   R⁶ of Formula (XLII) is selected from —NHC(═O)R⁷, —C(═O)NHR⁷,        —NHS(═O)2R⁷, —S(═O)₂NHR⁷; —NHC(═O)NHR⁷, —NHS(═O)₂NHR⁷,        —(C₁-C₃alkyl)-NHC(═O)R⁷, —(C₁-C₃alkyl)-C(═O)NHR⁷,        —(C₁-C₃alkyl)-NHS(═O)₂R⁷, —(C₁-C₃alkyl)-S(═O)₂NHR⁷;        —(C₁-C₃alkyl)-NHC(═O)NHR⁷, —(C₁-C₃alkyl)-NHS(═O)₂NHR⁷,        substituted or unsubstituted C₂-C₁₀heterocycloalkyl, or        substituted or unsubstituted heteroaryl;    -   each R⁷ of —NHC(═O)R⁷, —C(═O)NHR⁷, —NHS(═O)2R⁷, —S(═O)₂NHR⁷;        —NHC(═O)NHR⁷, —NHS(═O)₂NHR⁷, —(C₁-C₃alkyl)-NHC(═O)R⁷,        —(C₁-C₃alkyl)-C(═O)NHR⁷, —(C₁-C₃alkyl)-NHS(═O)2R⁷,        —(C₁-C₃alkyl)-S(═O)2NHR⁷; —(C₁-C₃alkyl)-NHC(═O)NHR⁷,        —(C₁-C₃alkyl)-NHS(═O)2NHR⁷ is independently selected from        C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆heteroalkyl, a substituted or        unsubstituted C3-C10cycloalkyl, a substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, a substituted or unsubstituted aryl, a        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₁₀cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C2-C10heterocycloalkyl, —C1-C6alkyl-(substituted or        unsubstituted aryl), —C₁-C₆alkyl-(substituted or unsubstituted        heteroaryl), —(CH2)p-CH(substituted or unsubstituted aryl)2,        —(CH₂)p-CH(substituted or unsubstituted heteroaryl)2,        —(CH₂)_(P)—CH(substituted or unsubstituted aryl)(substituted or        unsubstituted heteroaryl), -(substituted or unsubstituted        aryl)-(substituted or unsubstituted aryl), -(substituted or        unsubstituted aryl)-(substituted or unsubstituted heteroaryl),        -(substituted or unsubstituted heteroaryl)-(substituted or        unsubstituted aryl), or -(substituted or unsubstituted        heteroaryl)-(substituted or unsubstituted heteroaryl);    -   p of R⁷ is selected from 0, 1 or 2;    -   R^(8a), R^(8b), R^(8c), and R^(8d) of C(R^(8a))(R^(8b)) and        C(R^(8c))(R^(8d)) are independently selected from H, C₁-C₆alkyl,        C₁-C₆fluoroalkyl, C₁-C₆ alkoxy, C₁-C₆heteroalkyl, and        substituted or unsubstituted aryl;    -   or:    -   R^(8a) and R^(8d) are as defined above, and R^(8b) and R^(8c)        together form a bond;    -   or:    -   R^(8a) and R^(8d) are as defined above, and R^(8b) and R^(8c)        together with the atoms to which they are attached form a        substituted or unsubstituted fused 5-7 membered saturated, or        partially saturated carbocyclic ring or heterocyclic ring        comprising 1-3 heteroatoms selected from S, O and N, a        substituted or unsubstituted fused 5-10 membered aryl ring, or a        substituted or unsubstituted fused 5-10 membered heteroaryl ring        comprising 1-3 heteroatoms selected from S, O and N;    -   or:    -   R^(8c) and R^(8d) are as defined above, and R^(8a) and R^(8b)        together with the atoms to which they are attached form a        substituted or unsubstituted saturated, or partially saturated        3-7 membered spirocycle or heterospirocycle comprising 1-3        heteroatoms selected from S, O and N;    -   or:    -   R^(8a) and R^(8b) are as defined above, and R^(8c) and R^(8d)        together with the atoms to which they are attached form a        substituted or unsubstituted saturated, or partially saturated        3-7 membered spirocycle or heterospirocycle comprising 1-3        heteroatoms selected from S, O and N;    -   where each substituted alkyl, heteroalkyl, fused ring,        spirocycle, heterospirocycle, cycloalkyl, heterocycloalkyl, aryl        or heteroaryl is substituted with 1-3 R⁹; and    -   each R⁹ of R^(8a), R^(8b), R^(8c) and R^(8d) is independently        selected from halogen, —OH, —SH, (C═O), CN, C₁-C₄alkyl,        C1-C4fluoroalkyl, C₁-C₄ alkoxy, C₁-C₄ fluoroalkoxy, —NH₂,        —NH(C₁-C₄alkyl), —NH(C₁-C₄alkyl)₂, —C(═O)OH, —C(═O)NH₂,        —C(═O)C₁-C₃alkyl, —S(═O)₂CH₃, —NH(C₁-C₄alkyl)-OH,        —NH(C₁-C₄alkyl)-O—(C₁-C₄alkyl), —O(C₁-C₄alkyl)-NH₂;        —O(C₁-C₄alkyl)-NH—(C₁-C₄alkyl), and        —O(C₁-C₄alkyl)-N—(C₁-C₄alkyl)2, or two R⁹ together with the        atoms to which they are attached form a methylene dioxy or        ethylene dioxy ring substituted or unsubstituted with halogen,        —OH, or C₁-C₃alkyl.

In any of the compounds described herein, the ILM can have the structureof Formula (XLIII), which is derived from the IAP ligands described inWO Pub. No. 2013/071039, or an unnatural mimetic thereof:

wherein:

-   -   W¹ of Formula (XLIII) is selected from O, S, N—R^(A), or        C(R^(8a))(R^(8b));    -   W² of Formula (XLIII) is selected from O, S, N—R^(A), or        C(R^(8c))(R^(8d)); provided that W¹ and W² are not both 0, or        both S;    -   R¹ of Formula (XLIII) is selected from H, C₁-C₆alkyl,        C₃-C₆cycloalkyl, —C₁-C₆alkyl-(substituted or unsubstituted        C₃-C₆cycloalkyl), substituted or unsubstituted aryl, substituted        or unsubstituted heteroaryl, —C₁-C₆alkyl-(substituted or        unsubstituted aryl), or —C₁-C₆alkyl-(substituted or        unsubstituted heteroaryl);    -   when X¹ of Formula (XLIII) is selected from N—R^(A), S, S(O), or        S(O)₂, then X² of Formula (XLIII) is CR^(2c)R^(2d), and X³ of        Formula (XLIII) is CR^(2a)R^(2b);    -   or:    -   when X¹ of Formula (XLIII) is O, then X² of Formula (XLIII) is        selected from O, N—R^(A), S, S(O), or S(O)₂, and X³ of        Formula (XLIII) is CR^(2a)R^(2b);    -   or:    -   when X¹ of Formula (XLIII) is CR^(2e)R^(2f) and X² of        Formula (XLIII) is CR^(2c)R^(2d), and R^(2e) and R^(2c) together        form a bond, and X³ of Formula (XLIII) is CR^(2a)R^(2b);    -   or:    -   X¹ and X² of Formula (XLIII) are independently selected from C        and N, and are members of a fused substituted or unsubstituted        saturated or partially saturated 3-10 membered cycloalkyl ring,        a fused substituted or unsubstituted saturated or partially        saturated 3-10 membered heterocycloalkyl ring, a fused        substituted or unsubstituted 5-10 membered aryl ring, or a fused        substituted or unsubstituted 5-10 membered heteroaryl ring, and        X³ of Formula (XLIII) is CR^(2a)R^(2b);    -   or:    -   X² and X³ of Formula (XLIII) are independently selected from C        and N, and are members of a fused substituted or unsubstituted        saturated or partially saturated 3-10 membered cycloalkyl ring,        a fused substituted or unsubstituted saturated or partially        saturated 3-10 membered heterocycloalkyl ring, a fused        substituted or unsubstituted 5-10 membered aryl ring, or a fused        substituted or unsubstituted 5-10 membered heteroaryl ring, and        X¹ of Formula (VLII) is CR^(2e)R^(2f);    -   R^(A) of N—R^(A) is H, C₁-C₆alkyl, —C(═O)C₁-C₂alkyl, substituted        or unsubstituted aryl, or substituted or unsubstituted        heteroaryl;    -   R^(2a), R^(2b), R^(2c), R^(2d), R^(2e), and R^(2f) of        CR^(2c)R^(2d), CR^(2a)R^(2b) and CR^(2e)R^(2f) are independently        selected from H, substituted or unsubstituted C₁-C₆alkyl,        substituted or unsubstituted C₁-C₆heteroalkyl, substituted or        unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted        C₂-C₅heterocycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), —C₁-C₆alkyl-(substituted or unsubstituted        heteroaryl) and —C(═O)R^(B);    -   R^(B) of —C(═O)R^(B) is substituted or unsubstituted C₁-C₆alkyl,        substituted or unsubstituted C₃-C₆cycloalkyl, substituted or        unsubstituted C₂-C₅heterocycloalkyl, substituted or        unsubstituted aryl, substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), —C₁-C₆alkyl-(substituted or unsubstituted        heteroaryl), or —NR^(D)R^(E);    -   R^(D) and R^(E) of NR^(D)R^(E) are independently selected from        H, substituted or unsubstituted C₁-C₆alkyl, substituted or        unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted        C₂-C₅heterocycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), or —C₁-C₆alkyl-(substituted or        unsubstituted heteroaryl);    -   m of Formula (XLIII) is 0, 1 or 2;    -   —U— of Formula (XLIII) is —NHC(═O)—, —C(═O)NH—, —NHS(═O)₂—,        —S(═O)₂NH—, —NHC(═O)NH—, —NH(C═O)O—, —O(C═O)NH—, or        —NHS(═O)₂NH—;    -   R³ of Formula (XLIII) is C₁-C₃alkyl, or C₁-C₃fluoroalkyl;    -   R⁴ of Formula (XLIII) is —NHR⁵, —N(R⁵)₂, —N+(R⁵)₃ or —OR⁵;    -   each R⁵ of —NHR⁵, —N(R⁵)₂, —N+(R⁵)₃ and —OR⁵ is independently        selected from H, C₁-C₃alkyl, C₁-C₃haloalkyl, C₁-C₃heteroalkyl        and —C₁-C₃alkyl-(C₃-C₅cycloalkyl);    -   or:    -   R³ and R⁵ of Formula (XLIII) together with the atoms to which        they are attached form a substituted or unsubstituted 5-7        membered ring;    -   or:    -   R³ of Formula (XLIII) is bonded to a nitrogen atom of U to form        a substituted or unsubstituted 5-7 membered ring;    -   R⁶ of Formula (XLIII) is selected from —NHC(═O)R⁷, —C(═O)NHR⁷,        —NHS(═O)2R⁷, —S(═O)₂NHR⁷; —NHC(═O)NHR⁷, —NHS(═O)₂NHR⁷,        —(C₁-C₃alkyl)-NHC(═O)R⁷, —(C₁-C₃alkyl)-C(═O)NHR⁷,        —(C₁-C₃alkyl)-NHS(═O)₂R⁷, —(C₁-C₃alkyl)-S(═O)₂NHR⁷;        —(C₁-C₃alkyl)-NHC(═O)NHR⁷, —(C₁-C₃alkyl)-NHS(═O)₂NHR⁷,        substituted or unsubstituted C₂-C₁₀heterocycloalkyl, or        substituted or unsubstituted heteroaryl;    -   each R⁷ of —NHC(═O)R⁷, —C(═O)NHR⁷, —NHS(═O)2R⁷, —S(═O)₂NHR⁷;        —NHC(═O)NHR⁷, —NHS(═O)₂NHR⁷, —(C₁-C₃alkyl)-NHC(═O)R⁷,        —(C₁-C₃alkyl)-C(═O)NHR⁷, —(C₁-C₃alkyl)-NHS(═O)2R⁷,        —(C₁-C₃alkyl)-S(═O)2NHR⁷; —(C₁-C₃alkyl)-NHC(═O)NHR⁷,        —(C₁-C₃alkyl)-NHS(═O)2NHR⁷ is independently selected from        C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆heteroalkyl, a substituted or        unsubstituted C3-C10cycloalkyl, a substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, a substituted or unsubstituted aryl, a        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₁₀cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C2-C10heterocycloalkyl, —C1-C6alkyl-(substituted or        unsubstituted aryl), —C₁-C₆alkyl-(substituted or unsubstituted        heteroaryl), —(CH₂)p-CH(substituted or unsubstituted aryl)2,        —(CH₂)p-CH(substituted or unsubstituted heteroaryl)2,        —(CH₂)_(P)—CH(substituted or unsubstituted aryl)(substituted or        unsubstituted heteroaryl), -(substituted or unsubstituted        aryl)-(substituted or unsubstituted aryl), -(substituted or        unsubstituted aryl)-(substituted or unsubstituted heteroaryl),        -(substituted or unsubstituted heteroaryl)-(substituted or        unsubstituted aryl), or -(substituted or unsubstituted        heteroaryl)-(substituted or unsubstituted heteroaryl);    -   p of R⁷ is 0, 1 or 2;    -   R^(8a), R^(8b), R^(8c), and R^(8d) of C(R^(8a))(R^(8b)) and        C(R^(8c))(R^(8d)) are independently selected from H, C₁-C₆alkyl,        C₁-C₆fluoroalkyl, C₁-C₆ alkoxy, C₁-C₆heteroalkyl, and        substituted or unsubstituted aryl;    -   or:    -   R^(8a) and R^(8d) are as defined above, and R^(8b) and R^(8c)        together form a bond;    -   or:    -   R^(8a) and R^(8d) are as defined above, and R^(8b) and R^(8c)        together with the atoms to which they are attached form a        substituted or unsubstituted fused 5-7 membered saturated, or        partially saturated carbocyclic ring or heterocyclic ring        comprising 1-3 heteroatoms selected from S, O and N, a        substituted or unsubstituted fused 5-10 membered aryl ring, or a        substituted or unsubstituted fused 5-10 membered heteroaryl ring        comprising 1-3 heteroatoms selected from S, O and N;    -   or:    -   R^(8c) and R^(8d) are as defined above, and R^(8a) and R^(8b)        together with the atoms to which they are attached form a        substituted or unsubstituted saturated, or partially saturated        3-7 membered spirocycle or heterospirocycle comprising 1-3        heteroatoms selected from S, O and N;    -   or:    -   R^(8a) and R^(8b) are as defined above, and R^(8c) and R^(8d)        together with the atoms to which they are attached form a        substituted or unsubstituted saturated, or partially saturated        3-7 membered spirocycle or heterospirocycle comprising 1-3        heteroatoms selected from S, O and N;    -   where each substituted alkyl, heteroalkyl, fused ring,        spirocycle, heterospirocycle, cycloalkyl, heterocycloalkyl, aryl        or heteroaryl is substituted with 1-3 R⁹; and    -   each R⁹ of R^(8a), R^(8b), R^(8c) and R^(8d) is independently        selected from halogen, —OH, —SH, (C═O), CN, C₁-C₄alkyl,        C1-C4fluoroalkyl, C₁-C₄ alkoxy, C₁-C₄ fluoroalkoxy, —NH₂,        —NH(C₁-C₄alkyl), —NH(C₁-C₄alkyl)₂, —C(═O)OH, —C(═O)NH₂,        —C(═O)C₁-C₃alkyl, —S(═O)₂CH₃, —NH(C₁-C₄alkyl)-OH,        —NH(C₁-C₄alkyl)-O—(C₁-C₄alkyl), —O(C₁-C₄alkyl)-NH2;        —O(C₁-C₄alkyl)-NH—(C₁-C₄alkyl), and        —O(C₁-C₄alkyl)-N—(C₁-C₄alkyl)₂, or two R⁹ together with the        atoms to which they are attached form a methylene dioxy or        ethylene dioxy ring substituted or unsubstituted with halogen,        —OH, or C₁-C₃alkyl.

In any of the compounds described herein, the ILM can have the structureof Formula (XLIV), which is derived from the IAP ligands described in WOPub. No. 2013/071039, or an unnatural mimetic thereof:

wherein:

-   -   W¹ of Formula (XLIV) is selected from O, S, N—R^(A), or        C(R^(8a))(R^(8b));    -   W² of Formula (XLIV) is selected from O, S, N—R^(A), or        C(R^(8c))(R^(8d)); provided that W¹ and W² are not both O, or        both S;    -   W³ of Formula (XLIV) is selected from O, S, N—R^(A), or        C(R^(8e))(R^(8f)), providing that the ring comprising W¹, W²,        and W³ does not comprise two adjacent oxygen atoms or sulfur        atoms;    -   R¹ of Formula (XLIV) is selected from H, C₁-C₆alkyl,        C₃-C₆cycloalkyl, —C₁-C₆alkyl-(substituted or unsubstituted        C₃-C₆cycloalkyl), substituted or unsubstituted aryl, substituted        or unsubstituted heteroaryl, —C₁-C₆alkyl-(substituted or        unsubstituted aryl), or —C₁-C₆alkyl-(substituted or        unsubstituted heteroaryl);    -   when X¹ of Formula (XLIV) is O, then X² of Formula (XLIV) is        selected from CR^(2c)R^(2d) and N—R^(A), and X³ of        Formula (XLIV) is CR^(2a)R^(2b);    -   or:    -   when X¹ of Formula (XLIV) is CH₂, then X² of Formula (XLIV) is        selected from O, N—R^(A), S, S(O), or S(O)₂, and X³ of        Formula (XLIV) is CR^(2a)R^(2b);    -   or:    -   when X¹ of Formula (XLIV) is CR^(2e)R^(2f) and X² of        Formula (XLIV) is CR^(2c)R^(2d), and R^(2e) and R^(2c) together        form a bond, and X³ of Formula (VLIV) is CR^(2a)R^(2b);    -   or:    -   X¹ and X³ of Formula (XLIV) are both CH₂ and X² of        Formula (XLII) is C═O, C═C(R^(c))2, or C═NR^(C); where each        R^(C) is independently selected from H, —CN, —OH, alkoxy,        substituted or unsubstituted C₁-C₆alkyl, substituted or        unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted        C₂-C₅heterocycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), or —C₁-C₆alkyl-(substituted or        unsubstituted heteroaryl);    -   or:    -   X¹ and X² of Formula (XLIV) are independently selected from C        and N, and are members of a fused substituted or unsubstituted        saturated or partially saturated 3-10 membered cycloalkyl ring,        a fused substituted or unsubstituted saturated or partially        saturated 3-10 membered heterocycloalkyl ring, a fused        substituted or unsubstituted 5-10 membered aryl ring, or a fused        substituted or unsubstituted 5-10 membered heteroaryl ring, and        X³ of Formula (XLIV) is CR^(2a)R^(2b);    -   or:    -   X² and X³ of Formula (XLIV) are independently selected from C        and N, and are members of a fused substituted or unsubstituted        saturated or partially saturated 3-10 membered cycloalkyl ring,        a fused substituted or unsubstituted saturated or partially        saturated 3-10 membered heterocycloalkyl ring, a fused        substituted or unsubstituted 5-10 membered aryl ring, or a fused        substituted or unsubstituted 5-10 membered heteroaryl ring, and        X¹ of Formula (VLIV) is CR^(2e)R^(2f);    -   R^(A) of N—R^(A) is selected from H, C₁-C₆alkyl,        —C(═O)C₁-C₂alkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R^(2a), R^(2b), R^(2c), R^(2d), R^(2e), and R²¹ of        CR^(2c)R^(2d), CR^(2a)R^(2b) and CR^(2e)R^(2f) are independently        selected from H, substituted or unsubstituted C₁-C₆alkyl,        substituted or unsubstituted C₁-C₆heteroalkyl, substituted or        unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted        C₂-C₅heterocycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), —C₁-C₆alkyl-(substituted or unsubstituted        heteroaryl) and —C(═O)R^(B);    -   R^(B) of —C(═O)R^(B) is selected from substituted or        unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₃-C₆cycloalkyl, substituted or unsubstituted        C₂-C₅heterocycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), —C₁-C₆alkyl-(substituted or unsubstituted        heteroaryl), or —NR^(D)R^(E);    -   R^(D) and R^(E) of NR^(D)R^(E) are independently selected from        H, substituted or unsubstituted C₁-C₆alkyl, substituted or        unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted        C₂-C₅heterocycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl,        —C₁-C₆alkyl-(substituted or unsubstituted C₃-C₆cycloalkyl),        —C₁-C₆alkyl-(substituted or unsubstituted        C₂-C₅heterocycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted aryl), or —C₁-C₆alkyl-(substituted or        unsubstituted heteroaryl);    -   m of Formula (XLIV) is selected from 0, 1 or 2;    -   —U— of Formula (XLIV) is selected from —NHC(═O)—, —C(═O)NH—,        —NHS(═O)₂—, —S(═O)₂NH—, —NHC(═O)NH—, —NH(C═O)O—, —O(C═O)NH—, or        —NHS(═O)₂NH—;    -   R³ of Formula (XLIV) is selected from C₁-C₃alkyl, or        C₁-C₃fluoroalkyl;    -   R⁴ of Formula (XLIV) is selected from —NHR⁵, —N(R⁵)₂, —N+(R⁵)₃        or —OR⁵;    -   each R⁵ of —NHR⁵, —N(R⁵)₂, —N+(R⁵)₃ and —OR⁵ is independently        selected from H, C₁-C₃alkyl, C₁-C₃haloalkyl, C₁-C₃heteroalkyl        and —C₁-C₃alkyl-(C₃-C₅cycloalkyl);    -   or:    -   R³ and R⁵ of Formula (XLIV) together with the atoms to which        they are attached form a substituted or unsubstituted 5-7        membered ring;    -   or:    -   R³ of Formula (XLIII) is bonded to a nitrogen atom of U to form        a substituted or unsubstituted 5-7 membered ring;    -   R⁶ of Formula (XLIII) is selected from —NHC(═O)R⁷, —C(═O)NHR⁷,        —NHS(═O)2R⁷, —S(═O)₂NHR⁷; —NHC(═O)NHR⁷, —NHS(═O)₂NHR⁷,        —(C₁-C₃alkyl)-NHC(═O)R⁷, —(C₁-C₃alkyl)-C(═O)NHR⁷,        —(C₁-C₃alkyl)-NHS(═O)₂R⁷, —(C₁-C₃alkyl)-S(═O)₂NHR⁷;        —(C₁-C₃alkyl)-NHC(═O)NHR⁷, —(C₁-C₃alkyl)-NHS(═O)₂NHR⁷,        substituted or unsubstituted C₂-C₁₀heterocycloalkyl, or        substituted or unsubstituted heteroaryl;    -   each R⁷ of —NHC(═O)R⁷, —C(═O)NHR⁷, —NHS(═O)2R⁷, —S(═O)₂NHR⁷;        —NHC(═O)NHR⁷, —NHS(═O)₂NHR⁷, —(C₁-C₃alkyl)-NHC(═O)R⁷,        —(C₁-C₃alkyl)-C(═O)NHR⁷, —(C₁-C₃alkyl)-NHS(═O)2R⁷,        —(C₁-C₃alkyl)-S(═O)2NHR⁷; —(C₁-C₃alkyl)-NHC(═O)NHR⁷,        —(C₁-C₃alkyl)-NHS(═O)2NHR⁷ is independently selected from        C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆heteroalkyl, a substituted or        unsubstituted C3-C10cycloalkyl, a substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, a substituted or unsubstituted aryl, a        substituted or unsubstituted heteroaryl, i-C₆alkyl-(substituted        or unsubstituted C₃-C₁₀cycloalkyl), —C₁-C₆alkyl-(substituted or        unsubstituted C2-C10heterocycloalkyl, —C1-C6alkyl-(substituted        or unsubstituted aryl), —C₁-C₆alkyl-(substituted or        unsubstituted heteroaryl), —(CH2)p-CH(substituted or        unsubstituted aryl)2, —(CH₂)p-CH(substituted or unsubstituted        heteroaryl)2, —(CH₂)_(P)—CH(substituted or unsubstituted        aryl)(substituted or unsubstituted heteroaryl), -(substituted or        unsubstituted aryl)-(substituted or unsubstituted aryl),        -(substituted or unsubstituted aryl)-(substituted or        unsubstituted heteroaryl), -(substituted or unsubstituted        heteroaryl)-(substituted or unsubstituted aryl), or        -(substituted or unsubstituted heteroaryl)-(substituted or        unsubstituted heteroaryl);    -   p of R⁷ is selected from 0, 1 or 2;    -   R^(8a), R^(8b), R^(8c), R^(8d), R^(8e), and R⁸¹ of        C(R^(8a))(R^(8b)), C(R^(8c))(R^(8d)) and C(R^(8e))(R^(8f)) are        independently selected from H, C₁-C₆alkyl, C₁-C₆fluoroalkyl,        C₁-C₆ alkoxy, C₁-C₆heteroalkyl, and substituted or unsubstituted        aryl;    -   or:    -   R^(8a), R^(8d), R^(8e), and R^(8f) of C(R^(8a))(R^(8b)),        C(R^(8c))(R^(8d)) and C(R^(8e))(R^(8f)) are as defined above,        and R^(8b) and R^(8c) together form a bond;    -   or:    -   R^(8a), R^(8b), R^(8d), and R^(8f) of C(R^(8a))(R^(8b)),        C(R^(8c))(R^(8d)) and C(R^(8e))(R^(8f)) are as defined above,        and R^(8c) and R^(8e) together form a bond;    -   or:    -   R^(8a), R^(8d), R^(8e), and R^(8f) of C(R^(8a))(R^(8b)),        C(R^(8c))(R^(8d)) and C(R^(8e))(R^(8f)) are as defined above,        and R^(8b) and R^(8c) together with the atoms to which they are        attached form a substituted or unsubstituted fused 5-7 membered        saturated, or partially saturated carbocyclic ring or        heterocyclic ring comprising 1-3 heteroatoms selected from S, O        and N, a substituted or unsubstituted fused 5-10 membered aryl        ring, or a substituted or unsubstituted fused 5-10 membered        heteroaryl ring comprising 1-3 heteroatoms selected from S, O        and N;    -   or:    -   R^(8a), R^(8b), R^(8d), and R^(8f) of C(R^(8a))(R^(8b)),        C(R^(8c))(R^(8d)) and C(R^(8e))(R^(8f)) are as defined above,        and R^(8c) and R^(8e) together with the atoms to which they are        attached form a substituted or unsubstituted fused 5-7 membered        saturated, or partially saturated carbocyclic ring or        heterocyclic ring comprising 1-3 heteroatoms selected from S, O        and N, a substituted or unsubstituted fused 5-10 membered aryl        ring, or a substituted or unsubstituted fused 5-10 membered        heteroaryl ring comprising 1-3 heteroatoms selected from S, O        and N;    -   or:    -   R^(8c), R^(8d), R^(8e), and R^(8f) of C(R^(8c))(R^(8d)) and        C(R^(8e))(R^(8f)) are as defined above, and R^(8a) and R^(8b)        together with the atoms to which they are attached form a        substituted or unsubstituted saturated, or partially saturated        3-7 membered spirocycle or heterospirocycle comprising 1-3        heteroatoms selected from S, O and N;    -   or:    -   R^(8a), R^(8b), R^(8e), and R^(8f) of C(R^(8a))(R^(8b)) and        C(R^(8e))(R^(8f)) are as defined above, and R^(8c) and R^(8d)        together with the atoms to which they are attached form a        substituted or unsubstituted saturated, or partially saturated        3-7 membered spirocycle or heterospirocycle comprising 1-3        heteroatoms selected from S, O and N;    -   or:    -   R^(8a), R^(8b), R^(8c), and R^(8d) of C(R^(8a))(R^(8b)) and        C(R^(8c))(R^(8d)) are as defined above, and R^(8e) and R^(8f)        together with the atoms to which they are attached form a        substituted or unsubstituted saturated, or partially saturated        3-7 membered spirocycle or heterospirocycle comprising 1-3        heteroatoms selected from S, O and N;    -   or:    -   where each substituted alkyl, heteroalkyl, fused ring,        spirocycle, heterospirocycle, cycloalkyl, heterocycloalkyl, aryl        or heteroaryl is substituted with 1-3 R⁹; and    -   each R⁹ of R^(8a), R^(8b), R^(8c), R^(8d), R^(8e), and R^(8f) is        independently selected from halogen, —OH, —SH, (C═O), CN,        C₁-C₄alkyl, C₁-C₄fluoroalkyl, C₁-C₄ alkoxy, C₁-C₄ fluoroalkoxy,        —NH₂, —NH(C₁-C₄alkyl), —NH(C₁-C₄alkyl)₂, —C(═O)OH, —C(═O)NH₂,        —C(═O)C₁-C₃alkyl, —S(═O)₂CH₃, —NH(C₁-C₄alkyl)-OH,        —NH(C₁-C₄alkyl)-O—(C₁-C₄alkyl), —O(C₁-C₄alkyl)-NH2;        —O(C₁-C₄alkyl)-NH—(C₁-C₄alkyl), and        —O(C₁-C₄alkyl)-N—(C₁-C₄alkyl)2, or two R⁹ together with the        atoms to which they are attached form a methylene dioxy or        ethylene dioxy ring substituted or unsubstituted with halogen,        —OH, or C₁-C₃alkyl.

In any of the compounds described herein, the ILM can have the structureof Formula (XLV), (XLVI) or (XLVII), which is derived from the IAPligands described in Vamos, M., et al., Expedient synthesis of highlypotent antagonists of inhibitor of apoptosis proteins (IAPs) with uniqueselectivity for ML-IAP, ACS Chem. Biol., 8(4), 725-32 (2013), or anunnatural mimetic thereof:

wherein:

-   -   R², R³ and R⁴ of Formula (XLV) are independently selected from H        or ME;    -   X of Formula (XLV) is independently selected from O or S; and    -   R¹ of Formula (XLV) is selected from:

In a particular embodiment, the ILM has a structure according to Formula(XLVIII):

wherein R³ and R⁴ of Formula (XLVIII) are independently selected from Hor ME;

is a 5-member heterocycle selected from:

In a particular embodiment, the

of Formula XLVIII) is

In a particular embodiment, the ILM has a structure and attached to alinker group L as shown below:

In a particular embodiment, the ILM has a structure according to Formula(XLIX), (L), or (LI):

wherein:R³ of Formula (XLIX), (L) or (LI) are independently selected from H orME;

is a 5-member heterocycle selected from:

andL of Formula (XLIX), (L) or (LI) is selected from:

In a particular embodiment, L of Formula (XLIX), (L), or (LI)

In a particular embodiment, the ILM has a structure according to Formula(LII):

In a particular embodiment, the ILM according to Formula (LII) ischemically linked to the linker group L in the area denoted with

and as shown below:

In any of the compounds described herein, the ILM can have the structureof Formula (LIII) or (LIV), which is based on the TAP ligands describedin Hennessy, E J, et al., Discovery of aminopiperidine-based Smacmimetics as IAP antagonists, Bioorg. Med. Chem. Lett., 22(4), 1960-4(2012), or an unnatural mimetic thereof:

wherein:

-   -   R¹ of Formulas (LIII) and (LIV) is selected from:

-   -   R² of Formulas (LIII) and (LIV) is selected from H or Me;    -   R³ of Formulas (LIII) and (LIV) is selected from:

-   -   X of is selected from H, halogen, methyl, methoxy, hydroxy,        nitro or trifluoromethyl.

In any of the compounds described herein, the ILM can have the structureof and be chemically linked to the linker as shown in Formula (LV) or(LVI), or an unnatural mimetic thereof:

In any of the compounds described herein, the ILM can have the structureof Formula (LVII), which is based on the IAP ligands described in Cohen,F, et al., Orally bioavailable antagonists of inhibitor of apoptosisproteins based on an azabicyclooctane scaffold, J. Med. Chem., 52(6),1723-30 (2009), or an unnatural mimetic thereof:

wherein:

-   -   R¹ of Formulas (LVII) is selected from:

-   -   X of

is selected from H, fluoro, methyl or methoxy.

In a particular embodiment, the ILM is represented by the followingstructure:

In a particular embodiment, the ILM is selected from the groupconsisting of, and which the chemical link between the ILM and linkergroup L is shown:

In any of the compounds described herein, the ILM is selected from thegroup consisting of the structures below, which are based on the IAPligands described in Asano, M, et al., Design, sterioselectivesynthesis, and biological evaluation of novel tri-cyclic compounds asinhibitor of apoptosis proteins (IAP) antagonists, Bioorg. Med. Chem.,21(18): 5725-37 (2013), or an unnatural mimetic thereof:

In a particular embodiment, the ILM is selected from the groupconsisting of, and which the chemical link between the ILM and linkergroup L is shown:

In any of the compounds described herein, the ILM can have the structureof Formula (LVIII), which is based on the IAP ligands described inAsano, M, et al., Design, sterioselective synthesis, and biologicalevaluation of novel tri-cyclic compounds as inhibitor of apoptosisproteins (IAP) antagonists, Bioorg. Med. Chem., 21(18): 5725-37 (2013),or an unnatural mimetic thereof:

wherein X of Formula (LVIII) is one or two substituents independentlyselected from H, halogen or cyano.

In any of the compounds described herein, the ILM can have the structureof and be chemically linked to the linker group L as shown in Formula(LIX) or (LX), or an unnatural mimetic thereof:

wherein X of Formula (LIX) and (LX) is one or two substituentsindependently selected from H, halogen or cyano, and; and L of Formulas(LIX) and (LX) is a linker group as described herein.

In any of the compounds described herein, the ILM can have the structureof Formula (LXI), which is based on the IAP ligands described inArdecky, R J, et al., Design, synthesis and evaluation of inhibitor ofapoptosis (IAP) antagonists that are highly selective for the BIR2domain of XIAP, Bioorg. Med. Chem., 23(14): 4253-7 (2013), or anunnatural mimetic thereof:

of Formula (LXI) is a natural or unnatural amino acid; andR² of Formula (LXI) is selected from:

In any of the compounds described herein, the ILM can have the structureof and be chemically linked to the linker group L as shown in Formula(LXII) or (LLXIII), or an unnatural mimetic thereof:

of Formula (LXI) is a natural or unnatural amino acid; and L of Formula(LXI) is a linker group as described herein.

In any of the compounds described herein, the ILM can have the structureselected from the group consisting of, which is based on the IAP ligandsdescribed in Wang, J, et al., Discovery of novel secondmitochondrial-derived activator of caspase mimetics as selectiveinhibitor or apoptosis protein inhibitors, J. Pharmacol. Exp. Ther.,349(2): 319-29 (2014), or an unnatural mimetic thereof:

In any of the compounds described herein, the ILM has a structureaccording to Formula (LXIX), which is based on the IAP ligands describedin Hird, A W, et al., Structure-based design and synthesis of tricyclicIAP (Inhibitors of Apoptosis Proteins) inhibitors, Bioorg. Med. Chem.Lett., 24(7) 1820-4 (2014), or an unnatural mimetic thereof:

wherein R of Formula LIX is selected from the group consisting of:

R1 of

is selected from H or Me;R2 of

is selected from alkyl or cycloalkyl;X of

is 1-2 substitutents independently selected from halogen, hydroxy,methoxy, nitro and trifluoromethylZ of

is O or NH;HET of

is mono- or fused bicyclic heteroaryl; and- - - of Formula (LIX) is an optional double bond.

In a particular embodiment, the ILM of the compound has a chemicalstructure as represented by:

In a particular embodiment, the ILM of the compound has a chemicalstructure selected from the group consisting of:

The term “independently” is used herein to indicate that the variable,which is independently applied, varies independently from application toapplication.

The term “alkyl” shall mean within its context a linear, branch-chainedor cyclic fully saturated hydrocarbon radical or alkyl group, preferablya C₁-C₁₀, more preferably a C₁-C₆, alternatively a C₁-C₃ alkyl group,which may be optionally substituted. Examples of alkyl groups aremethyl, ethyl, n-butyl, sec-butyl, n-hexyl, n-heptyl, n-octyl, n-nonyl,n-decyl, isopropyl, 2-methylpropyl, cyclopropyl, cyclopropylmethyl,cyclobutyl, cyclopentyl, cyclopentylethyl, cyclohexylethyl andcyclohexyl, among others. In certain embodiments, the alkyl group isend-capped with a halogen group (At, Br, Cl, F, or I). In certainpreferred embodiments, compounds according to the present disclosurewhich may be used to covalently bind to dehalogenase enzymes. Thesecompounds generally contain a side chain (often linked through apolyethylene glycol group) which terminates in an alkyl group which hasa halogen substituent (often chlorine or bromine) on its distal endwhich results in covalent binding of the compound containing such amoiety to the protein.

The term “Alkenyl” refers to linear, branch-chained or cyclic C₂-C₁₀(preferably C₂-C₆) hydrocarbon radicals containing at least one C═Cbond.

The term “Alkynyl” refers to linear, branch-chained or cyclic C₂-C₁₀(preferably C₂-C₆) hydrocarbon radicals containing at least one C≡Cbond.

The term “alkylene” when used, refers to a —(CH₂)_(n)— group (n is aninteger generally from 0-6), which may be optionally substituted. Whensubstituted, the alkylene group preferably is substituted on one or moreof the methylene groups with a C₁-C₆ alkyl group (including acyclopropyl group or a t-butyl group), but may also be substituted withone or more halo groups, preferably from 1 to 3 halo groups or one ortwo hydroxyl groups, 0-(C₁-C₆ alkyl) groups or amino acid sidechains asotherwise disclosed herein. In certain embodiments, an alkylene groupmay be substituted with a urethane or alkoxy group (or other group)which is further substituted with a polyethylene glycol chain (of from 1to 10, preferably 1 to 6, often 1 to 4 ethylene glycol units) to whichis substituted (preferably, but not exclusively on the distal end of thepolyethylene glycol chain) an alkyl chain substituted with a singlehalogen group, preferably a chlorine group. In still other embodiments,the alkylene (often, a methylene) group, may be substituted with anamino acid sidechain group such as a sidechain group of a natural orunnatural amino acid, for example, alanine, β-alanine, arginine,asparagine, aspartic acid, cysteine, cystine, glutamic acid, glutamine,glycine, phenylalanine, histidine, isoleucine, lysine, leucine,methionine, proline, serine, threonine, valine, tryptophan or tyrosine.

The term “unsubstituted” shall mean substituted only with hydrogenatoms. A range of carbon atoms which includes C₀ means that carbon isabsent and is replaced with H. Thus, a range of carbon atoms which isC₀-C₆ includes carbons atoms of 1, 2, 3, 4, 5 and 6 and for C₀, H standsin place of carbon.

The term “substituted” or “optionally substituted” shall meanindependently (i.e., where more than substituent occurs, eachsubstituent is independent of another substituent) one or moresubstituents (independently up to five substituents, preferably up tothree substituents, often 1 or 2 substituents on a moiety in a compoundaccording to the present disclosure and may include substituents whichthemselves may be further substituted) at a carbon (or nitrogen)position anywhere on a molecule within context, and includes assubstituents hydroxyl, thiol, carboxyl, cyano (C≡N), nitro (NO₂),halogen (preferably, 1, 2 or 3 halogens, especially on an alkyl,especially a methyl group such as a trifluoromethyl), an alkyl group(preferably, C₁-C₁₀, more preferably, C₁-C₆), aryl (especially phenyland substituted phenyl for example benzyl or benzoyl), alkoxy group(preferably, C₁-C₆ alkyl or aryl, including phenyl and substitutedphenyl), thioether (C₁-C₆ alkyl or aryl), acyl (preferably, C₁-C₆ acyl),ester or thioester (preferably, C₁-C₆ alkyl or aryl) including alkyleneester (such that attachment is on the alkylene group, rather than at theester function which is preferably substituted with a C₁-C₆ alkyl oraryl group), preferably, C₁-C₆ alkyl or aryl, halogen (preferably, F orC₁), amine (including a five- or six-membered cyclic alkylene amine,further including a C₁-C₆ alkyl amine or a C₁-C₆ dialkyl amine whichalkyl groups may be substituted with one or two hydroxyl groups) or anoptionally substituted —N(C₀-C₆ alkyl)C(O)(O—C₁-C₆ alkyl) group (whichmay be optionally substituted with a polyethylene glycol chain to whichis further bound an alkyl group containing a single halogen, preferablychlorine substituent), hydrazine, amido, which is preferably substitutedwith one or two C₁-C₆ alkyl groups (including a carboxamide which isoptionally substituted with one or two C₁-C₆ alkyl groups), alkanol(preferably, C₁-C₆ alkyl or aryl), or alkanoic acid (preferably, C₁-C₆alkyl or aryl). Substituents according to the present disclosure mayinclude, for example —SiR₁R₂R₃ groups where each of R₁ and R₂ is asotherwise described herein and R₃ is H or a C₁-C₆ alkyl group,preferably R₁, R₂, R₃ in this context is a C₁-C₃ alkyl group (includingan isopropyl or t-butyl group). Each of the above-described groups maybe linked directly to the substituted moiety or alternatively, thesubstituent may be linked to the substituted moiety (preferably in thecase of an aryl or heteroaryl moiety) through an optionally substituted—(CH₂)_(m) or alternatively an optionally substituted —(OCH₂)_(m)—,—(OCH₂CH₂)_(m) or —(CH₂CH₂O)_(m) group, which may be substituted withany one or more of the above-described substituents. Alkylene groups—(CH₂)_(m) or —(CH₂)_(n)— groups or other chains such as ethylene glycolchains, as identified above, may be substituted anywhere on the chain.Preferred substituents on alkylene groups include halogen or C₁-C₆(preferably C₁-C₃) alkyl groups, which may be optionally substitutedwith one or two hydroxyl groups, one or two ether groups (O—C₁-C₆groups), up to three halo groups (preferably F), or a sidechain of anamino acid as otherwise described herein and optionally substitutedamide (preferably carboxamide substituted as described above) orurethane groups (often with one or two C₀-C₆ alkyl substituents, whichgroup(s) may be further substituted). In certain embodiments, thealkylene group (often a single methylene group) is substituted with oneor two optionally substituted C₁-C₆ alkyl groups, preferably C₁-C₄ alkylgroup, most often methyl or O-methyl groups or a sidechain of an aminoacid as otherwise described herein. In the present disclosure, a moietyin a molecule may be optionally substituted with up to fivesubstituents, preferably up to three substituents. Most often, in thepresent disclosure moieties which are substituted are substituted withone or two substituents.

The term “substituted” (each substituent being independent of any othersubstituent) shall also mean within its context of use C₁-C₆ alkyl,C₁-C₆ alkoxy, halogen, amido, carboxamido, sulfone, includingsulfonamide, keto, carboxy, C₁-C₆ester (oxyester or carbonylester),C₁-C₆keto, urethane —O—C(O)—NR₁R₂ or —N(R₁)—C(O)—O—R¹, nitro, cyano andamine (especially including a C₁-C₆ alkylene-NR¹R², a mono- or di-C₁-C₆alkyl substituted amines which may be optionally substituted with one ortwo hydroxyl groups). Each of these groups contain unless otherwiseindicated, within context, between 1 and 6 carbon atoms. In certainembodiments, preferred substituents will include for example, —NH—,—NHC(O)—, —O—, ═O, —(CH₂)_(m) (here, m and n are in context, 1, 2, 3, 4,5 or 6), —S—, —S(O)—, SO₂— or —NH—C(O)—NH—, —(CH₂)_(n)OH, —(CH₂)_(n)SH,—(CH₂)_(n)COOH, C₁-C₆ alkyl, —(CH₂)_(n)O—(C₁-C₆ alkyl),—(CH₂)_(n)C(O)—(C₁-C₆ alkyl), —(CH₂)_(n)OC(O)—(C₁-C₆ alkyl),—(CH₂)_(n)C(O)O—(C₁-C₆ alkyl), —(CH₂)_(n)NHC(O)—R₁,—(CH₂)_(n)C(O)—NR₁R₂, —(OCH₂)_(n)OH, —(CH₂O)_(n)COOH, C₁-C₆ alkyl,—(OCH₂)_(n)O—(C₁-C₆ alkyl), —(CH₂O)_(n)C(O)—(C₁-C₆ alkyl),—(OCH₂)_(n)NHC(O)—R₁, —(CH₂O)_(n)C(O)—NR₁R₂, —S(O)₂—R_(S), —S(O)—R₅(R_(S) is C₁-C₆ alkyl or a —(CH₂)_(m)—NR¹R₂ group), NO₂, CN or halogen(F, C₁, Br, I, preferably F or C₁), depending on the context of the useof the substituent. R₁ and R₂ are each, within context, H or a C₁-C₆alkyl group (which may be optionally substituted with one or twohydroxyl groups or up to three halogen groups, preferably fluorine). Theterm “substituted” shall also mean, within the chemical context of thecompound defined and substituent used, an optionally substituted aryl orheteroaryl group or an optionally substituted heterocyclic group asotherwise described herein. Alkylene groups may also be substituted asotherwise disclosed herein, preferably with optionally substitutedC₁-C₆alkyl groups (methyl, ethyl or hydroxymethyl or hydroxyethyl ispreferred, thus providing a chiral center), a sidechain of an amino acidgroup as otherwise described herein, an amido group as describedhereinabove, or a urethane group O—C(O)—NR₁R₂ group where R₁ and R₂ areas otherwise described herein, although numerous other groups may alsobe used as substituents. Various optionally substituted moieties may besubstituted with 3 or more substituents, preferably no more than 3substituents and preferably with 1 or 2 substituents. It is noted thatin instances where, in a compound at a particular position of themolecule substitution is required (principally, because of valency), butno substitution is indicated, then that substituent is construed orunderstood to be H, unless the context of the substitution suggestsotherwise.

The term “aryl” or “aromatic”, in context, refers to a substituted (asotherwise described herein) or unsubstituted monovalent aromatic radicalhaving a single ring (e.g., benzene, phenyl, benzyl) or condensed rings(e.g., naphthyl, anthracenyl, phenanthrenyl, etc.) and can be bound tothe compound according to the present disclosure at any available stableposition on the ring(s) or as otherwise indicated in the chemicalstructure presented. Other examples of aryl groups, in context, mayinclude heterocyclic aromatic ring systems, “heteroaryl” groups havingone or more nitrogen, oxygen, or sulfur atoms in the ring (moncyclic)such as imidazole, furyl, pyrrole, furanyl, thiene, thiazole, pyridine,pyrimidine, pyrazine, triazole, oxazole or fused ring systems such asindole, quinoline, indolizine, azaindolizine, benzofurazan, etc., amongothers, which may be optionally substituted as described above. Amongthe heteroaryl groups which may be mentioned include nitrogen-containingheteroaryl groups such as pyrrole, pyridine, pyridone, pyridazine,pyrimidine, pyrazine, pyrazole, imidazole, triazole, triazine,tetrazole, indole, isoindole, indolizine, azaindolizine, purine,indazole, quinoline, dihydroquinoline, tetrahydroquinoline,isoquinoline, dihydroisoquinoline, tetrahydroisoquinoline, quinolizine,phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline,pteridine, imidazopyridine, imidazotriazine, pyrazinopyridazine,acridine, phenanthridine, carbazole, carbazoline, pyrimidine,phenanthroline, phenacene, oxadiazole, benzimidazole, pyrrolopyridine,pyrrolopyrimidine and pyridopyrimidine; sulfur-containing aromaticheterocycles such as thiophene and benzothiophene; oxygen-containingaromatic heterocycles such as furan, pyran, cyclopentapyran, benzofuranand isobenzofuran; and aromatic heterocycles comprising 2 or more heteroatoms selected from among nitrogen, sulfur and oxygen, such as thiazole,thiadizole, isothiazole, benzoxazole, benzothiazole, benzothiadiazole,phenothiazine, isoxazole, furazan, phenoxazine, pyrazoloxazole,imidazothiazole, thienofuran, furopyrrole, pyridoxazine, furopyridine,furopyrimidine, thienopyrimidine and oxazole, among others, all of whichmay be optionally substituted.

The term “substituted aryl” refers to an aromatic carbocyclic groupcomprised of at least one aromatic ring or of multiple condensed ringsat least one of which being aromatic, wherein the ring(s) aresubstituted with one or more substituents. For example, an aryl groupcan comprise a substituent(s) selected from: —(CH₂)_(n)OH,—(CH₂)_(n)—O—(C₁-C₆)alkyl, —(CH₂)_(n)—O—(CH₂)_(n)—(C₁-C₆)alkyl,—(CH₂)_(n)—C(O)(C₀-C₆) alkyl, —(CH₂)_(n)—C(O)O(C₀-C₆)alkyl,—(CH₂)_(n)—OC(O)(C₀-C₆)alkyl, amine, mono- or di-(C₁-C₆ alkyl) aminewherein the alkyl group on the amine is optionally substituted with 1 or2 hydroxyl groups or up to three halo (preferably F, C₁) groups, OH,COOH, C₁-C₆ alkyl, preferably CH₃, CF₃, OMe, OCF₃, NO₂, or CN group(each of which may be substituted in ortho-, meta- and/or para-positionsof the phenyl ring, preferably para-), an optionally substituted phenylgroup (the phenyl group itself is connected/coupled to a PTM group,including a ULM group via a linker group), and/or at least one of F, C₁,OH, COOH, CH₃, CF₃, OMe, OCF₃, NO₂, or CN group (in ortho-, meta- and/orpara-positions of the phenyl ring, preferably para-), a naphthyl group,which may be optionally substituted, an optionally substitutedheteroaryl, preferably an optionally substituted isoxazole including amethylsubstituted isoxazole, an optionally substituted oxazole includinga methylsubstituted oxazole, an optionally substituted thiazoleincluding a methyl substituted thiazole, an optionally substitutedisothiazole including a methyl substituted isothiazole, an optionallysubstituted pyrrole including a methylsubstituted pyrrole, an optionallysubstituted imidazole including a methylimidazole, an optionallysubstituted benzimidazole or methoxybenzylimidazole, an optionallysubstituted oximidazole or methyloximidazole, an optionally substituteddiazole group, including a methyldiazole group, an optionallysubstituted triazole group, including a methylsubstituted triazolegroup, an optionally substituted pyridine group, including a halo-(preferably, F) or methylsubstitutedpyridine group or an oxapyridinegroup (where the pyridine group is linked to the phenyl group by anoxygen), an optionally substituted furan, an optionally substitutedbenzofuran, an optionally substituted dihydrobenzofuran, an optionallysubstituted indole, indolizine or azaindolizine (2, 3, or4-azaindolizine), an optionally substituted quinoline, and combinationsthereof.

“Carboxyl” denotes the group —C(O)OR, where R is hydrogen, alkyl,substituted alkyl, aryl, substituted aryl, heteroaryl or substitutedheteroaryl, whereas these generic substituents have meanings which areidentical with definitions of the corresponding groups defined herein.

The term “heteroaryl” or “hetaryl” can mean but is in no way limited toan optionally substituted quinoline (which may be attached to thepharmacophore or substituted on any carbon atom within the quinolinering), an optionally substituted indole (including dihydroindole), anoptionally substituted indolizine, an optionally substitutedazaindolizine (2, 3 or 4-azaindolizine) an optionally substitutedbenzimidazole, benzodiazole, benzoxofuran, an optionally substitutedimidazole, an optionally substituted isoxazole, an optionallysubstituted oxazole (preferably methyl substituted), an optionallysubstituted diazole, an optionally substituted triazole, a tetrazole, anoptionally substituted benzofuran, an optionally substituted thiophene,an optionally substituted thiazole (preferably methyl and/or thiolsubstituted), an optionally substituted isothiazole, an optionallysubstituted triazole (preferably a 1,2,3-triazole substituted with amethyl group, a triisopropylsilyl group, an optionally substituted—(CH₂)_(m)—O—C₁-C₆ alkyl group or an optionally substituted—(CH₂)_(m)—C(O)—O—C₁-C₆ alkyl group), an optionally substituted pyridine(2-, 3, or 4-pyridine) or a group according to the chemical structure:

wherein:

-   -   S^(c) is CHR^(SS), NR^(URE), or O;    -   R^(HET) is H, CN, NO₂, halo (preferably Cl or F), optionally        substituted C₁-C₆ alkyl (preferably substituted with one or two        hydroxyl groups or up to three halo groups (e.g. CF₃),        optionally substituted O(C₁-C₆ alkyl) (preferably substituted        with one or two hydroxyl groups or up to three halo groups) or        an optionally substituted acetylenic group —C≡C—R_(a) where        R_(a) is H or a C₁-C₆ alkyl group (preferably C₁-C₃ alkyl);    -   R^(SS) is H, CN, NO₂, halo (preferably F or C₁), optionally        substituted C₁-C₆ alkyl (preferably substituted with one or two        hydroxyl groups or up to three halo groups), optionally        substituted O—(C₁-C₆ alkyl) (preferably substituted with one or        two hydroxyl groups or up to three halo groups) or an optionally        substituted —C(O)(C₁-C₆ alkyl) (preferably substituted with one        or two hydroxyl groups or up to three halo groups);    -   R^(URE) is H, a C₁-C₆ alkyl (preferably H or C₁-C₃ alkyl) or a        —C(O)(C₁-C₆ alkyl), each of which groups is optionally        substituted with one or two hydroxyl groups or up to three        halogen, preferably fluorine groups, or an optionally        substituted heterocycle, for example piperidine, morpholine,        pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine,        piperazine, each of which is optionally substituted, and    -   Y^(C) is N or C—R^(YC), where R^(YC) is H, OH, CN, NO₂, halo        (preferably Cl or F), optionally substituted C₁-C₆ alkyl        (preferably substituted with one or two hydroxyl groups or up to        three halo groups (e.g. CF₃), optionally substituted O(C₁-C₆        alkyl) (preferably substituted with one or two hydroxyl groups        or up to three halo groups) or an optionally substituted        acetylenic group —C≡C—R_(a) where R_(a) is H or a C₁-C₆ alkyl        group (preferably C₁-C₃ alkyl).

The terms “aralkyl” and “heteroarylalkyl” refer to groups that compriseboth aryl or, respectively, heteroaryl as well as alkyl and/orheteroalkyl and/or carbocyclic and/or heterocycloalkyl ring systemsaccording to the above definitions.

The term “arylalkyl” as used herein refers to an aryl group as definedabove appended to an alkyl group defined above. The arylalkyl group isattached to the parent moiety through an alkyl group wherein the alkylgroup is one to six carbon atoms. The aryl group in the arylalkyl groupmay be substituted as defined above.

The term “Heterocycle” refers to a cyclic group which contains at leastone heteroatom, e.g., N, O or S, and may be aromatic (heteroaryl) ornon-aromatic. Thus, the heteroaryl moieties are subsumed under thedefinition of heterocycle, depending on the context of its use.Exemplary heteroaryl groups are described hereinabove.

Exemplary heterocyclics include: azetidinyl, benzimidazolyl,1,4-benzodioxanyl, 1,3-benzodioxolyl, benzoxazolyl, benzothiazolyl,benzothienyl, dihydroimidazolyl, dihydropyranyl, dihydrofuranyl,dioxanyl, dioxolanyl, ethyleneurea, 1,3-dioxolane, 1,3-dioxane,1,4-dioxane, furyl, homopiperidinyl, imidazolyl, imidazolinyl,imidazolidinyl, indolinyl, indolyl, isoquinolinyl, isothiazolidinyl,isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl, naphthyridinyl,oxazolidinyl, oxazolyl, pyridone, 2-pyrrolidone, pyridine, piperazinyl,N-methylpiperazinyl, piperidinyl, phthalimide, succinimide, pyrazinyl,pyrazolinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl,quinolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydroquinoline,thiazolidinyl, thiazolyl, thienyl, tetrahydrothiophene, oxane, oxetanyl,oxathiolanyl, thiane among others.

Heterocyclic groups can be optionally substituted with a member selectedfrom the group consisting of alkoxy, substituted alkoxy, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl,acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy,oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxy,carboxyalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol,thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl,heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino,nitro, —SO-alkyl, —SO-substituted alkyl, —SOaryl, —SO-heteroaryl,—SO2-alkyl, —SO2-substituted alkyl, —SO2-aryl, oxo (═O), and—SO2-heteroaryl. Such heterocyclic groups can have a single ring ormultiple condensed rings. Examples of nitrogen heterocycles andheteroaryls include, but are not limited to, pyrrole, imidazole,pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine,isoindole, indole, indazole, purine, quinolizine, isoquinoline,quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline,cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine,phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine,phenothiazine, imidazolidine, imidazoline, piperidine, piperazine,indoline, morpholino, piperidinyl, tetrahydrofuranyl, and the like aswell as N-alkoxy-nitrogen containing heterocycles. The term“heterocyclic” also includes bicyclic groups in which any of theheterocyclic rings is fused to a benzene ring or a cyclohexane ring oranother heterocyclic ring (for example, indolyl, quinolyl, isoquinolyl,tetrahydroquinolyl, and the like).

The term “cycloalkyl” can mean but is in no way limited to univalentgroups derived from monocyclic or polycyclic alkyl groups orcycloalkanes, as defined herein, e.g., saturated monocyclic hydrocarbongroups having from three to twenty carbon atoms in the ring, including,but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl and the like. The term “substituted cycloalkyl” can mean butis in no way limited to a monocyclic or polycyclic alkyl group and beingsubstituted by one or more substituents, for example, amino, halogen,alkyl, substituted alkyl, carbyloxy, carbylmercapto, aryl, nitro,mercapto or sulfo, whereas these generic substituent groups havemeanings which are identical with definitions of the correspondinggroups as defined in this legend.

“Heterocycloalkyl” refers to a monocyclic or polycyclic alkyl group inwhich at least one ring carbon atom of its cyclic structure beingreplaced with a heteroatom selected from the group consisting of N, O, Sor P. “Substituted heterocycloalkyl” refers to a monocyclic orpolycyclic alkyl group in which at least one ring carbon atom of itscyclic structure being replaced with a heteroatom selected from thegroup consisting of N, O, S or P and the group is containing one or moresubstituents selected from the group consisting of halogen, alkyl,substituted alkyl, carbyloxy, carbylmercapto, aryl, nitro, mercapto orsulfo, whereas these generic substituent group have meanings which areidentical with definitions of the corresponding groups as defined inthis legend.

The term “hydrocarbyl” shall mean a compound which contains carbon andhydrogen and which may be fully saturated, partially unsaturated oraromatic and includes aryl groups, alkyl groups, alkenyl groups andalkynyl groups.

The term “independently” is used herein to indicate that the variable,which is independently applied, varies independently from application toapplication.

The term “lower alkyl” refers to methyl, ethyl or propyl

The term “lower alkoxy” refers to methoxy, ethoxy or propoxy.

In any of the embodiments described herein, the W, X, Y, Z, G, G′, R,R′, R″, Q1-Q4, A, and Rn can independently be covalently coupled to alinker and/or a linker to which is attached one or more PTM, ULM, ILM orILM′ groups.

Exemplary MLMs

In certain additional embodiments, the MLM of the bifunctional compoundcomprises chemical moieties such as substituted imidazolines,substituted spiro-indolinones, substituted pyrrolidines, substitutedpiperidinones, substituted morpholinones, substitutedpyrrolopyrimidines, substituted imidazolopyridines, substitutedthiazoloimidazoline, substituted pyrrolopyrrolidinones, and substitutedisoquinolinones.

In additional embodiments, the MLM comprises the core structuresmentioned above with adjacent bis-aryl substitutions positioned as cis-or trans-configurations.

In still additional embodiments, the MLM comprises part of structuralfeatures as in RG7112, RG7388, SAR405838, AMG-232, AM-7209, DS-5272,MK-8242, and NVP-CGM-097, and analogs or derivatives thereof.

In certain preferred embodiments, MLM is a derivative of substitutedimidazoline represented as Formula (A-1), or thiazoloimidazolinerepresented as Formula (A-2), or spiro indolinone represented as Formula(A-3), or pyrollidine represented as Formula (A-4), orpiperidinone/morphlinone represented as Formula (A-5), or isoquinolinonerepresented as Formula (A-6), or pyrollopyrimidine/imidazolopyridinerepresented as Formula (A-7), orpyrrolopyrrolidinone/imidazolopyrrolidinone represented as Formula(A-8).

-   -   wherein above Formula (A-1) through Formula (A-8),    -   X of Formula (A-1) through Formula (A-8) is selected from the        group consisting of carbon,    -   oxygen, sulfur, sulfoxide, sulfone, and N—R^(a);        -   R^(a) is independently H or an alkyl group with carbon            number 1 to 6;    -   Y and Z of Formula (A-1) through Formula (A-8) are independently        carbon or nitrogen;    -   A, A′ and A″ of Formula (A-1) through Formula (A-8) are        independently selected from C, N, O or S, can also be one or two        atoms forming a fused bicyclic ring, or a 6,5- and 5,5-fused        aromatic bicyclic group;    -   R₁, R₂ of Formula (A-1) through Formula (A-8) are independently        selected from the group consisting of an aryl or heteroaryl        group, a heteroaryl group having one or two heteroatoms        independently selected from sulfur or nitrogen, wherein the aryl        or heteroaryl group can be mono-cyclic or bi-cyclic, or        unsubstituted or substituted with one to three substituents        independently selected from the group consisting of:        -   halogen, —CN, C1 to C6 alkyl group, C3 to C6 cycloalkyl,            —OH, alkoxy with 1 to 6 carbons, fluorine substituted alkoxy            with 1 to 6 carbons, sulfoxide with 1 to 6 carbons, sulfone            with 1 to 6 carbons, ketone with 2 to 6 carbons, amides with            2 to 6 carbons, and dialkyl amine with 2 to 6 carbons;    -   R₃, R₄ of Formula (A-1) through Formula (A-8) are independently        selected from the group consisting of H, methyl and C1 to C6        alkyl;    -   R₅ of Formula (A-1) through Formula (A-8) is selected from the        group consisting of an aryl or heteroaryl group, a heteroaryl        group having one or two heteroatoms independently selected from        sulfur or nitrogen, wherein the aryl or heteroaryl group can be        mono-cyclic or bi-cyclic, or unsubstituted or substituted with        one to three substituents independently selected from the group        consisting of:        -   halogen, —CN, C1 to C6 alkyl group, C3 to C6 cycloalkyl,            —OH, alkoxy with 1 to 6 carbons, fluorine substituted alkoxy            with 1 to 6 carbons, sulfoxide with 1 to 6 carbons, sulfone            with 1 to 6 carbons, ketone with 2 to 6 carbons, amides with            2 to 6 carbons, dialkyl amine with 2 to 6 carbons, alkyl            ether (C2 to C6), alkyl ketone (C3 to C6), morpholinyl,            alkyl ester (C3 to C6), alkyl cyanide (C3 to C6);    -   R₆ of Formula (A-1) through Formula (A-8) is H or —C(═O)R^(b),        wherein        -   R^(b) of Formula (A-1) through Formula (A-8) is selected            from the group consisting of alkyl, cycloalkyl, mono-, di-            or tri-substituted aryl or heteroaryl, 4-morpholinyl,            1-(3-oxopiperazunyl), 1-piperidinyl, 4-N—R^(c)-morpholinyl,            4-R^(c)-piperidinyl, and 3-R^(c)-piperidinyl, wherein        -   R^(c) of Formula (A-1) through Formula (A-8) is selected            from the group consisting of alkyl, fluorine substituted            alkyl, cyano alkyl, hydroxyl-substituted alkyl, cycloalkyl,            alkoxyalkyl, amide alkyl, alkyl sulfone, alkyl sulfoxide,            alkyl amide, aryl, heteroaryl, mono-, bis- and            tri-substituted aryl or heteroaryl, CH2CH2R^(d), and            CH2CH2CH2R^(d), wherein        -   R^(d) of Formula (A-1) through Formula (A-8) is selected            from the group consisting of alkoxy, alkyl sulfone, alkyl            sulfoxide, N-substituted carboxamide, —NHC(O)-alkyl,            —NH—SO₂-alkyl, aryl, substituted aryl, heteroaryl,            substituted heteroaryl;    -   R₇ of Formula (A-1) through Formula (A-8) is selected from the        group consisting of H, C1 to C6 alkyl, cyclic alkyl, fluorine        substituted alkyl, cyano substituted alkyl, 5- or 6-membered        hetero aryl or aryl, substituted 5- or 6-membered hetero aryl or        aryl;    -   R₈ of Formula (A-1) through Formula (A-8) is selected from the        group consisting of —R^(e)—C(O)—    -   R^(f), —R^(e)-alkoxy, —R^(e)-aryl, —R^(e)-heteroaryl, and        —R^(e)—C(O)—R^(f)—C(O)—R^(g), wherein:        -   R^(e) of Formula (A-1) through Formula (A-8) is an alkylene            with 1 to 6 carbons, or a bond;        -   R^(f) of Formula (A-1) through Formula (A-8) is a            substituted 4- to 7-membered heterocycle;        -   R^(g) of Formula (A-1) through Formula (A-8) is selected            from the group consisting of aryl, hetero aryl, substituted            aryl or heteroaryl, and 4- to 7-membered heterocycle;    -   R₉ of Formula (A-1) through Formula (A-8) is selected from the        group consisting of a mono-, bis- or tri-substituent on the        fused bicyclic aromatic ring in Formula (A-3), wherein the        substitutents are independently selected from the group        consisting of halogen, alkene, alkyne, alkyl, unsubstituted or        substituted with Cl or F;    -   R₁₀ of Formula (A-1) through Formula (A-8) is selected from the        group consisting of an aryl or heteroaryl group, wherein the        heteroaryl group can contain one or two heteroatoms as sulfur or        nitrogen, aryl or heteroaryl group can be mono-cyclic or        bi-cyclic, the aryl or heteroaryl group can be unsubstituted or        substituted with one to three substituents, including a halogen,        F, C₁, —CN, alkene, alkyne, C1 to C6 alkyl group, C1 to C6        cycloalkyl, —OH, alkoxy with 1 to 6 carbons, fluorine        substituted alkoxy with 1 to 6 carbons, sulfoxide with 1 to 6        carbons, sulfone with 1 to 6 carbons, ketone with 2 to 6        carbons;    -   R₁₁ of Formula (A-1) through Formula (A-8) is        —C(O)—N(R^(h))(R^(i)), wherein R^(h) and R^(i) are selected from        groups consisting of the following:        -   H, C1 to C6 alkyl, alkoxy substituted alkyl, sulfone            substituted alkyl, aryl, heteroaryl, mono-, bis- or            tri-substituted aryl or hetero aryl, alkyl carboxylic acid,            heteroaryl carboxylic acid, alkyl carboxylic acid, fluorine            substituted alkyl carboxylic acid, aryl substituted            cycloalkyl, hetero aryl substituted cycloalkyl; wherein        -   R^(h) and R^(i) of Formula (A-1) through Formula (A-8) are            independently selected from the group consisting of H,            connected to form a ring, 4-hydroxycyclohehexane; mono- and            di-hydroxy substituted alkyl (C3 to C6);            3-hydroxycyclobutane; phenyl-4-carboxylic acid, and            substituted phenyl-4-carboxylic acid;    -   R₁₂ and R₁₃ of Formula (A-1) through Formula (A-8) are        independently selected from H, lower alkyl (C1 to C6), lower        alkenyl (C2 to C6), lower alkynyl (C2 to C6), cycloalkyl (4, 5        and 6-membered ring), substituted cycloalkyl, cycloalkenyl,        substituted cycloalkenyl, 5- and 6-membered aryl and heteroaryl,        R¹² and R¹³ can be connected to form a 5- and 6-membered ring        with or without substitution on the ring;    -   R₁₄ of Formula (A-1) through Formula (A-8) is selected from the        group consisting of alkyl, substituted alkyl, alkenyl,        substituted alkenyl, aryl, substituted aryl, heteroaryl,        substituted heteroaryl, heterocycle, substituted heterocycle,        cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted        cycloalkenyl;    -   R₁₅ of Formula (A-1) through Formula (A-8) is CN;    -   R₁₆ of Formula (A-1) through Formula (A-8) is selected from the        group consisting of C1-6 alkyl, C1-6 cycloalkyl, C2-6 alkenyl,        C1-6 alkyl or C3-6 cycloalkyl with one or multiple hydrogens        replaced by fluorine, alkyl or cycloalkyl with one CH₂ replaced        by S(═O), —S, or —S(═O)₂, alkyl or cycloalkyl with terminal CH₃        replaced by S(═O)2N(alkyl)(alkyl), —C(═O)N(alkyl)(alkyl),        —N(alkyl)S(═O)2(alkyl), —C(═O)2(alkyl), —O(alkyl), C1-6 alkyl or        alkyl-cycloalkyl with hydron replaced by hydroxyl group, a 3 to        7 membered cycloalkyl or heterocycloalkyl, optionally containing        a —(C═O)— group, or a 5 to 6 membered aryl or heteroaryl group,        which heterocycloalkyl or heteroaryl group can contain from one        to three heteroatoms independently selected from O, N or S, and        the cycloalkyl, heterocycloalkyl, aryl or heteroaryl group can        be unsubstituted or substituted with from one to three        substituents independently selected from halogen, C1-6 alkyl        groups, hydroxylated C1-6 alkyl, C1-6 alkyl containing        thioether, ether, sulfone, sulfoxide, fluorine substituted ether        or cyano group;    -   R₁₇ of Formula (A-1) through Formula (A-8) is selected from the        group consisting of (CH₂)nC(O)NR^(k)R^(l), wherein R^(k) and        R^(l) are independently selected from H, C1-6 alkyl,        hydroxylated C1-6 alkyl, C1-6 alkoxy alkyl, C1-6 alkyl with one        or multiple hydrogens replaced by fluorine, C1-6 alkyl with one        carbon replaced by S(O), S(O)(O), C1-6 alkoxyalkyl with one or        multiple hydrogens replaced by fluorine, C1-6 alkyl with        hydrogen replaced by a cyano group, 5 and 6 membered aryl or        heteroaryl, alkyl aryl with alkyl group containing 1-6 carbons,        and alkyl heteroaryl with alkyl group containing 1-6 carbons,        wherein the aryl or heteroaryl group can be further substituted;    -   R₁₈ of Formula (A-1) through Formula (A-8) is selected from the        group consisting of substituted aryl, heteroaryl, alkyl,        cycloalkyl, the substitution is preferably —N(C1-4        alkyl)(cycloalkyl), —N(C1-4 alkyl)alkyl-cycloalkyl, and —N(C1-4        alkyl)[(alkyl)-(heterocycle-substituted)-cycloalkyl];    -   R₁₉ of Formula (A-1) through Formula (A-8) is selected from the        group consisting of aryl, heteroaryl, bicyclic heteroaryl, and        these aryl or heteroaryl groups can be substituted with halogen,        C1-6 alkyl, C1-6 cycloalkyl, CF₃, F, CN, alkyne, alkyl sulfone,        the halogen substitution can be mon- bis- or tri-substituted;    -   R₂₀ and R₂₁ of Formula (A-1) through Formula (A-8) are        independently selected from C1-6 alkyl, C1-6 cycloalkyl, C1-6        alkoxy, hydroxylated C1-6 alkoxy, and fluorine substituted C1-6        alkoxy, wherein R₂₀ and R₂₁ can further be connected to form a        5, 6 and 7-membered cyclic or heterocyclic ring, which can        further be substituted;    -   R₂₂ of Formula (A-1) through Formula (A-8) is selected from the        group consisting of H, C1-6 alkyl, C1-6 cycloalkyl, carboxylic        acid, carboxylic acid ester, amide, reverse amide, sulfonamide,        reverse sulfonamide, N-acyl urea, nitrogen-containing 5-membered        heterocycle, the 5-membered heterocycles can be further        substituted with C1-6 alkyl, alkoxy, fluorine-substituted alkyl,        CN, and alkylsulfone;    -   R₂₃ of Formula (A-1) through Formula (A-8) is selected from        aryl, heteroaryl, —O-aryl, —O— heteroaryl, —O-alkyl,        —O-alkyl-cycloalkyl, —NH-alkyl, —NH-alkyl-cycloalkyl,        —N(H)-aryl, —N(H)— heteroaryl, —N(alkyl)-aryl,        —N(alkyl)-heteroaryl, the aryl or heteroaryl groups can be        substituted with halogen, C1-6 alkyl, hydroxylated C1-6 alkyl,        cycloalkyl, fluorine-substituted C1-6 alkyl, CN, alkoxy, alkyl        sulfone, amide and sulfonamide;    -   R₂₄ of Formula (A-1) through Formula (A-8) is selected from the        group consisting of —CH₂—(C1-6 alkyl), —CH2-cycloalkyl,        —CH2-aryl, CH2-heteroaryl, where alkyl, cycloalkyl, aryl and        heteroaryl can be substituted with halogen, alkoxy, hydoxylated        alkyl, cyano-substituted alkyl, cycloalyl and substituted        cycloalkyl;    -   R₂₅ of Formula (A-1) through Formula (A-8) is selected from the        group consisting of C1-6 alkyl, C1-6 alkyl-cycloalkyl,        alkoxy-substituted alkyl, hydroxylated alkyl, aryl, heteroaryl,        substituted aryl or heteroaryl, 5,6, and 7-membered        nitrogen-containing saturated heterocycles, 5,6-fused and        6,6-fused nitrogen-containing saturated heterocycles and these        saturated heterocycles can be substituted with C1-6 alkyl,        fluorine-substituted C1-6 alkyl, alkoxy, aryl and heteroaryl        group;    -   R₂₆ of Formula (A-1) through Formula (A-8) is selected from the        group consisting of C1-6 alkyl, C3-6 cycloalkyl, the alkyl or        cycloalkyl can be substituted with —OH, alkoxy,        fluorine-substituted alkoxy, fluorine-substituted alkyl, —NH₂,        —NH-alkyl, NH—C(O)alkyl, —NH—S(O)₂-alkyl, and —S(O)₂-alkyl;    -   R₂₇ of Formula (A-1) through Formula (A-8) is selected from the        group consisting of aryl, heteroaryl, bicyclic heteroaryl,        wherein the aryl or heteroaryl groups can be substituted with        C1-6 alkyl, alkoxy, NH₂, NH-alkyl, halogen, or —CN, and the        substitution can be independently mono-, bis- and        tri-substitution;    -   R₂₈ of Formula (A-1) through Formula (A-8) is selected from the        group consisting of aryl, 5 and 6-membered heteroaryl, bicyclic        heteroaryl, cycloalkyl, saturated heterocycle such as        piperidine, piperidinone, tetrahydropyran, N-acyl-piperidine,        wherein the cycloalkyl, saturated heterocycle, aryl or        heteroaryl can be further substituted with —OH, alkoxy, mono-,        bis- or tri-substitution including halogen, —CN, alkyl sulfone,        and fluorine substituted alkyl groups; and    -   R^(1″) of Formula (A-1) through Formula (A-8) is selected from        the group consisting of alkyl, aryl substituted alkyl, alkoxy        substituted alkyl, cycloalkyl, aryl-substituted cycloalkyl, and        alkoxy substituted cycloalkyl.

In certain embodiments, the heterocycles in R^(f) and R⁹ of Formula(A-1) through Formula (A-8) are substituted pyrrolidine, substitutedpiperidine, substituted piperazine.

More specifically, non-limiting examples of MLMs include those shownbelow as well as those ‘hybrid’ molecules that arise from thecombination of 1 or more of the different features shown in themolecules below.

Using MLM in Formula A-1 through A-8, the following PROTACs can beprepared to target a particular protein for degradation, where “L” is aconnector (i.e. a linker group), and “PTM” is a ligand binding to atarget protein.

In certain embodiments, the description provides a bifunctional moleculecomprising a structure selected from the group consisting of:

wherein X, R^(a), Y, Z, A, A′, A″, R₁, R₂, R₃, R₄, R₅, R₆, R^(b), R^(c),R^(d), R₇, R^(e), R^(f), R^(g), R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆,R₁₇, R^(k), R^(l), R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, R₂₇,R₂₈, and R_(1″) are as defined herein with regard to Formulas (A-1)through (A-8).

In certain embodiments, the description provides bifunctional orchimeric molecules with the structure: PTM-L-MLM, wherein PTM is aprotein target binding moiety coupled to an MLM by L, wherein L is abond (i.e., absent) or a chemical linker. In certain embodiments, theMLM has a structure selected from the group consisting of A-1-1, A-1-2,A-1-3, and A-1-4:

-   -   wherein:    -   R1′ and R2′ of Formulas A-1-1 through A-1-4 (i.e., A-1-1, A-1-2,        A-1-3, and A-1-4) are independently selected from the group        consisting of F, Cl, Br, I, acetylene, CN, CF₃ and NO₂;    -   R3′ is selected from the group consisting of —OCH₃, —OCH₂CH₃,        —OCH₂CH₂F, —OCH₂CH₂OCH₃, and —OCH(CH₃)₂;    -   R4′ of Formulas A-1-1 through A-1-4 is selected from the group        consisting of H, halogen, —CH₃, —CF₃, —OCH₃, —C(CH₃)₃,        —CH(CH₃)₂, -cyclopropyl, —CN, —C(CH₃)₂₀H, —C(CH₃)₂OCH₂CH₃,        —C(CH₃)₂CH₂OH, —C(CH₃)₂CH₂OCH₂CH₃, —C(CH₃)₂CH₂OCH₂CH₂OH,        —C(CH₃)₂CH₂OCH₂CH₃, —C(CH₃)₂CN, —C(CH₃)₂C(O)CH₃,        —C(CH₃)₂C(O)NHCH₃, —C(CH₃)₂C(O)N(CH₃)₂, —SCH₃, —SCH₂CH₃,        —S(O)₂CH₃, —S(O₂)CH₂CH₃, —NHC(CH₃)₃, —N(CH₃)₂, pyrrolidinyl, and        4-morpholinyl;    -   R5′ of Formulas A-1-1 through A-1-4 is selected from the group        consisting of halogen, -cyclopropyl, —S(O)₂CH₃, —S(O)₂CH₂CH₃,        1-pyrrolidinyl, —NH₂, —N(CH₃)₂, and —NHC(CH₃)₃; and    -   R6′ of Formulas A-1-1 through A-1-4 is selected from the        structures presented below where the linker connection point is        indicated as “*”.    -   Beside R6′ as the point for linker attachment, R4′ can also        serve as the linker attachment position. In the case that R4′ is        the linker connection site, linker will be connected to the        terminal atom of R4′ groups shown above.

In certain embodiments, the linker connection position of Formulas A-1-1through A-1-4 is at least one of R4′ or R6′ or both.

In certain embodiments, R^(6′) of Formulas A-1-1 through A-1-4 isindependently selected from the group consisting of H,

wherein “*” indicates the point of attachment of the linker.

In certain embodiments, the linker of Formula A-4-1 through A-4-6 isattached to at least one of R1′, R2′, R3′, R4′, R5′, R6′, or acombination thereof.

In certain embodiments, the description provides bifunctional orchimeric molecules with the structure: PTM-L-MLM, wherein PTM is aprotein target binding moiety coupled to an MLM by L, wherein L is abond (i.e., absent) or a chemical linker. In certain embodiments, theMLM has a structure selected from the group consisting of A-4-1, A-4-2,A-4-3, A-4-4, A-4-5, and A-4-6:

-   -   wherein:    -   R7′ of Formula A-4-1 through A-4-6 (i.e., A-4-1, A-4-2, A-4-3,        A-4-4, A-4-5, and A-4-6) is a member selected from the group        consisting of halogen, mono-, and di- or tri-substituted        halogen;    -   R8′ of Formula A-4-1 through A-4-6 is selected from the group        consisting of H, —F, —Cl, —Br, —I, —CN, —NO₂, ethylnyl,        cyclopropyl, methyl, ethyl, isopropyl, vinyl, methoxy, ethoxy,        isopropoxy, —OH, other C1-6 alkyl, other C1-6 alkenyl, and C1-6        alkynyl, mono-, di- or tri-substituted;    -   R9′ of Formula A-4-1 through A-4-6 is selected from the group        consisting of alkyl, substituted alkyl, alkenyl, substituted        alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl,        hetero aryl, substituted heteroaryl, cycloalkyl, substituted        cycloalkyl, alkenyl, and substituted cycloalkenyl;    -   Z of Formula A-4-1 through A-4-6 is selected from the group        consisting of H, —OCH₃, —OCH₂CH₃, and halogen;    -   R10′ and R11′ of Formula A-4-1 through A-4-6 are each        independently selected from the group consisting of H,        (CH₂)_(n)—R′, (CH₂)_(n)—NR′R″, (CH₂)_(n)—NR′COR″,        (CH₂)_(n)—NR′SO₂R″, (CH₂)_(n)—COOH, (CH₂)_(n)—COOR′,        (CH)_(n)—CONR′R″, (CH₂)_(n)—OR′, (CH₂)_(n)—SR′, (CH₂)_(n)—SOR′,        (CH₂)_(n)—CH(OH)—R′, (CH₂)_(n)—COR′, (CH₂)_(n)—SO₂R′,        (CH₂)_(n)—SONR′R″, (CH₂)_(n)—SO₂NR′R″,        (CH₂CH₂O)_(m)—(CH₂)_(n)—R′, (CH₂CH₂O)_(m)—(CH₂)_(n)—OH,        (CH₂CH₂O)_(m)—(CH₂)_(n)—OR′, (CH₂CH₂O)_(m)—(CH₂)_(n)—NR′R″,        (CH₂CH₂O)_(m) (CH₂)_(n)—NR′COR″,        (CH₂CH₂O)_(m)(CH₂)_(n)—NR′SO₂R″, (CH₂CH₂O)_(m)(CH₂)_(n)—COOH,        (CH₂CH₂O)_(m)(CH₂)_(n)—COOR′, (CH₂CH₂O)_(m)—(CH₂)_(n)—CONR′R″,        (CH₂CH₂O)_(m)—(CH₂)_(n)—SO₂R′, (CH₂CH₂O)_(m)—(CH₂)_(n)—COR′,        (CH₂CH₂O)_(m)—(CH₂)_(n)—SONR′R″,        (CH₂CH₂O)_(m)—(CH₂)_(n)—SO₂NR′R″,        (CH₂)_(p)—(CH₂CH₂O)_(m)—(CH₂)_(n)R′,        (CH₂)_(p)—(CH₂CH₂O)_(m)—(CH₂)_(n)—OH,        (CH₂)_(p)—(CH₂CH₂O)_(m)—(CH₂)_(n)—OR′,        (CH₂)_(p)—(CH₂CH₂O)_(m)—(CH₂)_(n)—NR′R″,        (CH₂)_(p)—(CH₂CH₂O)_(m)—(CH₂)_(n)—NR′COR″,        (CH₂)_(p)—(CH₂CH₂O)_(m)—(CH₂)_(n)—NR′SO₂R″,        (CH₂)_(p)—(CH₂CH₂O)_(m)—(CH₂)_(n)—COOH, (CH₂)_(p)—(CH₂CH₂O)_(m)        (CH₂)_(n)—COOR′, (CH₂)_(p)—(CH₂CH₂O)_(m)—(CH₂)_(n)—CONR′R″,        (CH₂)_(p)—(CH₂CH₂O)_(m)—(CH₂)_(n)—SO₂R′,        (CH₂)_(p)—(CH₂CH₂O)_(m)—(CH₂)_(n)—COR′,        (CH₂)_(p)—(CH₂CH₂O)_(m)—(CH₂)_(n)—SONR′R″,        (CH₂)_(p)—(CH₂CH₂O)_(m)—(CH₂)_(n)—SO₂NR′R″, Aryl-(CH₂)_(n)—COOH,        and heteroaryl-alkyl-CO-alkyl-NR′R″m, wherein the alkyl may be        substituted with OR′, and heteroaryl-(CH₂)_(n)-heterocycle        wherein the heterocycle may optionally be substituted with        alkyl, hydroxyl, COOR′ and COR′; wherein R′ and R¹¹ are selected        from H, alkyl, alkyl substituted with halogen, hydroxyl, NH2,        NH(alkyl), N(alkyl)2, oxo, carboxy, cycloalkyl and heteroaryl;    -   m, n, and p are independently 0 to 6;    -   R12′ of Formula A-4-1 through A-4-6 is selected from the group        consisting of —O-(alkyl), —O-(alkyl)-alkoxy, —C(O)-(alkyl),        —C(OH)-alkyl-alkoxy, —C(O)—NH, —C(O)—NH-(alkyl),        —C(O)—N-(alkyl)2, —S(O)-(alkyl), S(O)2-(alkyl), —C(O)-(cyclic        amine), and —O-aryl-(alkyl), —O-aryl-(alkoxy);    -   R1″ of Formula A-4-1 through A-4-6 is selected from the group        consisting of alkyl, aryl substituted alkyl, alkoxy substituted        alkyl, cycloalkyl, aryl-substituted cycloalkyl, and alkoxy        substituted cycloalkyl.

In any of the aspects or embodiments described herein, the alkyl, alkoxyor the like can be a lower alkyl or lower alkoxy.

In certain embodiments, the linker connection position of Formula A-4-1through A-4-6 is at least one of Z, R8′, R9′, R10′, R11″, R12″, or R1″.

The method used to design chimeric molecules as presented in A-1-1through A-1-4, A-4-1 through A-4-6 can be applied to MLM with formulaA-2, A-3, A-5, A-6, A-7 and A-8, wherein the solvent exposed area in theMLM can be connected to linker “L” which will be attached to targetprotein ligand “PTM”, to construct PROTACs.

Exemplary MDM2 binding moieties include, but not limited, the following:

the HDM2/MDM2 inhibitors identified in Vassilev, et al., In vivoactivation of the p53 pathway by small-molecule antagonists of MDM2,SCIENCE vol:303, pag:844-848 (2004), and Schneekloth, et al., Targetedintracellular protein degradation induced by a small molecule: En routeto chemical proteomics, Bioorg. Med. Chem. Lett. 18 (2008) 5904-5908,including (or additionally) the compounds nutlin-3, nutlin-2, andnutlin-1 (derivatized) as described below, as well as all derivativesand analogs thereof:

(derivatized where a linker group L or a -(L-MLM) group is attached, forexample, at the methoxy group or as a hydroxyl group);

(derivatized where a linker group L or a -(L-MLM) group is attached, forexample, at the methoxy group or hydroxyl group); and

(derivatized where a linker group L or a -(L-MLM) group is attached, forexample, via the methoxy group or as a hydroxyl group).

Exemplary CLMs

Neo-Imide Compounds

In one aspect the description provides compounds useful for bindingand/or inhibiting cereblon. In certain embodiments, the compound isselected from the group consisting of chemical structures:

wherein:

-   -   W of Formulas (a) through (e) is independently selected from the        group CH₂, CHR, C═O, SO₂, NH, and N-alkyl;    -   X of Formulas (a) through (e) is independently selected from the        group O, S and H₂;    -   Y of Formulas (a) through (e) is independently selected from the        group CH₂, —C═CR′, NH, N-alkyl, N-aryl, N-hetaryl, N-cycloalkyl,        N-heterocyclyl, O, and S;    -   Z of Formulas (a) through (e) is independently selected from the        group O, and S or H₂ except that both X and Z cannot be H₂;    -   G and G′ of Formulas (a) through (e) are independently selected        from the group H, alkyl (linear, branched, optionally        substituted), OH, R′OCOOR, R′OCONRR″, CH₂-heterocyclyl        optionally substituted with R′, and benzyl optionally        substituted with R′;    -   Q1-Q4 of Formulas (a) through (e) represent a carbon C        substituted with a group independently selected from R′, N or        N-oxide;    -   A of Formulas (a) through (e) is independently selected from the        group H, alkyl (linear, branched, optionally substituted),        cycloalkyl, Cl and F;    -   R of Formulas (a) through (e) comprises, but is not limited to:        —CONR′R″, —OR′, —NR′R″, —SR′, —SO₂R′, —SO₂NR′R″, —CR′R″—,        —CR′NR′R″—, (—CR′O)_(n)R″, -aryl, -hetaryl, -alkyl (linear,        branched, optionally substituted), -cycloalkyl, -heterocyclyl,        —P(O)(OR′)R″, —P(O)R′R″, —OP(O)(OR′)R″, —OP(O)R′R″, —Cl, —F,        —Br, —I, —CF₃, —CN, —NR′SO₂NR′R″, —NR′CONR′R″, —CONR′COR″,        —NR′C(═N—CN)NR′R″, —C(═N—CN)NR′R″, —NR′C(═N—CN)R″,        —NR′C(═C—NO₂)NR′R″, —SO₂NR′COR″, —NO₂, —CO₂R′, —C(C═N—OR′)R″,        —CR′═CR′R″, —CCR′, —S(C═O)(C═N—R′)R″, —SF₅ and —OCF₃    -   R′ and R″ of Formulas (a) through (e) are independently selected        from a bond, H, alkyl, cycloalkyl, aryl, heteroaryl,        heterocyclic, —C(═O)R, heterocyclyl, each of which is optionally        substituted;    -   n of Formulas (a) through (e) is an integer from 1-10 (e.g.,        1-4);    -   of Formulas (a) through (e) represents a bond that may be        stereospecific ((R) or (S)) or non-stereospecific; and    -   R_(n) of Formulas (a) through (e) comprises 1-4 independent        functional groups or atoms.

Exemplary CLMs

In any of the compounds described herein, the CLM comprises a chemicalstructure selected from the group:

wherein:

-   -   W of Formulas (a) through (e) is independently selected from the        group CH₂, CHR, C═O, SO₂, NH, and N-alkyl;    -   X of Formulas (a) through (e) is independently selected from the        group O, S and H2;    -   Y of Formulas (a) through (e) is independently selected from the        group CH₂, —C═CR′, NH, N-alkyl, N-aryl, N-hetaryl, N-cycloalkyl,        N-heterocyclyl, O, and S;    -   Z of Formulas (a) through (e) is independently selected from the        group O, and S or H2 except that both X and Z cannot be H2;    -   G and G′ of Formulas (a) through (e) are independently selected        from the group H, alkyl (linear, branched, optionally        substituted), OH, R′OCOOR, R′OCONRR″, CH₂-heterocyclyl        optionally substituted with R′, and benzyl optionally        substituted with R′;    -   Q1-Q4 of Formulas (a) through (e) represent a carbon C        substituted with a group independently selected from R′, N or        N-oxide;    -   A of Formulas (a) through (e) is independently selected from the        group H, alkyl, cycloalkyl, Cl and F;    -   R of Formulas (a) through (e) comprises, but is not limited to:        —CONR′R″, —OR′, —NR′R″, —SR′, —SO₂R′, —SO₂NR′R″, —CR′R″—,        —CR′NR′R″—, -aryl, -hetaryl, -alkyl, -cycloalkyl, -heterocyclyl,        —P(O)(OR′)R″, —P(O)R′R″, —OP(O)(OR′)R″, —OP(O)R′R″, —Cl, —F,        —Br, —I, —CF3, —CN, —NR′SO₂NR′R″, —NR′CONR′R″, —CONR′COR″,        —NR′C(═N—CN)NR′R″, —C(═N—CN)NR′R″, —NR′C(═N—CN)R″,        —NR′C(═C—NO2)NR′R″, —SO₂NR′COR″, —NO₂, —CO2R′, —C(C═N—OR′)R″,        —CR′═CR′R″, —CCR′, —S(C═O)(C═N—R′)R″, —SF5 and —OCF3    -   R′ and R″ of Formulas (a) through (e) are independently selected        from a bond, H, alkyl, cycloalkyl, aryl, heteroaryl,        heterocyclic, —C(═O)R, heterocyclyl, each of which is optionally        substituted;    -   n of Formulas (a) through (e) is an integer from 1-10 (e.g.,        1-4);    -   of Formulas (a) through (e) represents a bond that may be        stereospecific ((R) or (S)) or non-stereospecific; and    -   Rn of Formulas (a) through (e) comprises 1-4 independent        functional groups or atoms, and optionally, one of which is        modified to be covalently joined to a PTM, a chemical linker        group (L), a ULM, CLM (or CLM′) or combination thereof.

In certain embodiments described herein, the CLM or ULM comprises achemical structure selected from the group:

wherein:

-   -   W of Formula (g) is independently selected from the group CH₂,        C═O, NH, and N-alkyl;    -   R of Formula (g) is independently selected from a H, methyl, or        optionally substituted alkyl (e.g., C1-C6 alkyl (linear,        branched, optionally substituted));    -   of Formula (g) represents a bond that may be stereospecific ((R)        or (S)) or non-stereospecific; and    -   Rn of Formula (g) comprises 1-4 independently selected        functional groups or atoms, and optionally, one of which is        modified to be covalently joined to a PTM, a chemical linker        group (L), a ULM, CLM (or CLM′) or combination thereof.

In any of the embodiments described herein, the W, X, Y, Z, G, G′, R,R′, R″, Q1-Q4, A, and Rn of Formulas (a) through (g) can independentlybe covalently coupled to a linker and/or a linker to which is attachedone or more PTM, ULM, CLM or CLM′ groups.

More specifically, non-limiting examples of CLMs include those shownbelow as well as those “hybrid” molecules that arise from thecombination of 1 or more of the different features shown in themolecules below.

In any of the compounds described herein, the CLM comprises a chemicalstructure selected from the group:

wherein:

-   -   W of Formulas (h) through (ab) is independently selected from        CH₂, CHR, C═O, SO₂, NH, and N-alkyl;    -   Q₁, Q₂, Q₃, Q₄, Q₅ of Formulas (h) through (ab) are        independently represent a carbon C substituted with a group        independently selected from R′, N or N-oxide;    -   R¹ of Formulas (h) through (ab) is selected from H, CN, C1-C3        alkyl;    -   R² of Formulas (h) through (ab) is selected from the group H,        CN, C1-C3 alkyl, CHF₂, CF₃, CHO;    -   R³ of Formulas (h) through (ab) is selected from H, alkyl,        substituted alkyl, alkoxy, substituted alkoxy;    -   R⁴ of Formulas (h) through (ab) is selected from H, alkyl,        substituted alkyl;    -   R⁵ of Formulas (h) through (ab) is H or lower alkyl;    -   X of Formulas (h) through (ab) is C, CH or N;    -   R′ of Formulas (h) through (ab) is selected from H, halogen,        alkyl, substituted alkyl, alkoxy, substituted alkoxy;    -   R of Formulas (h) through (ab) is H, OH, lower alkyl, lower        alkoxy, cyano, halogenated lower alkoxy, or halogenated lower        alkyl    -   of Formulas (h) through (ab) is a single or double bond; and the        CLM is covalently joined to a PTM, a chemical linker group (L),        a ULM, CLM (or CLM′)    -   or combination thereof.

In any aspect or embodiment described herein, the CLM or CLM′ iscovalently joined to a PTM, a chemical linker group (L), a ULM, a CLM, aCLM′, or a combination thereof via an R group (such as, R, R¹, R², R³,R⁴ or R′), W, X, or a Q group (such as, Q₁, Q₂, Q₃, Q₄, or Q₅) ofFormulas (h) through (ab).

In any of the embodiments described herein, the CLM or CLM′ iscovalently joined to a PTM, a chemical linker group (L), a ULM, a CLM, aCLM′, or a combination thereof via W, X, R, R¹, R², R³, R⁴, R⁵, R′, Q₁,Q₂, Q₃, Q₄, and Q₅ of Formulas (h) through (ab).

In any of the embodiments described herein, the W, X, R¹, R², R³, R⁴,R′, Q₁, Q₂, Q₃, Q₄, and Q₅ of Formulas (h) through (ab) canindependently be covalently coupled to a linker and/or a linker to whichis attached to one or more PTM, ULM, ULM′, CLM or CLM′ groups.

More specifically, non-limiting examples of CLMs include those shownbelow as well as “hybrid” molecules or compounds that arise fromcombining 1 or more features of the following compounds:

wherein:

-   -   W of Formulas (ac) through (an) is independently selected from        the group CH₂, CHR, C═O, SO₂, NH, and N-alkyl;    -   R¹ of Formulas (ac) through (an) is selected from the group H,        CN, C1-C3 alkyl;    -   R³ of Formulas (ac) through (an) is selected from H, alkyl,        substituted alkyl, alkoxy, substituted alkoxy;    -   R of Formulas (ac) through (an) is H;    -   is a single or double bond; and    -   Rn of Formulas (ac) through (an) comprises a functional group or        an atom.

In any of the embodiments described herein, the W, R¹, R², Q₁, Q₂, Q₃,Q₄, and Rn of Formulas (ac) through (an) can independently be covalentlycoupled to a linker and/or a linker to which is attached one or morePTM, ULM, ULM′, CLM or CLM′ groups.

In any of the embodiments described herein, the R¹, R², Q₁, Q₂, Q₃, Q₄,and Rn of Formulas (ac) through (an) can independently be covalentlycoupled to a linker and/or a linker to which is attached one or morePTM, ULM, ULM′, CLM or CLM′ groups.

In any of the embodiments described herein, the Q₁, Q₂, Q₃, Q₄, and Rnof Formulas (ac) through (an) can independently be covalently coupled toa linker and/or a linker to which is attached one or more PTM, ULM,ULM′, CLM or CLM′ groups.

In any aspect or embodiment described herein, R. of Formulas (ac)through (an) is modified to be covalently joined to the linker group(L), a PTM, a ULM, a second CLM having the same chemical structure asthe CLM, a CLM′, a second linker, or any multiple or combinationthereof.

In any aspect or embodiment described herein, the CLM is selected from:

wherein R′ is a halogen and R¹ is as described above with regard toFormulas (h) through (ab) or (ac) through (an).

In certain cases, the CLM can be imides that bind to cereblon E3 ligase.These imides and linker attachment point can be but not limited to thefollowing structures:

-   -   wherein    -   R′ is a halogen.

Exemplary VLMs

In certain embodiments of the compounds as described herein, ULM is VLMand comprises a chemical structure selected from the group ULM-a:

wherein:

-   -   where a dashed line indicates the attachment of at least one        PTM, another ULM or VLM or MLM or ILM or CLM (i.e., ULM′ or VLM′        or CLM′ or ILM′ or MLM′), or a chemical linker moiety coupling        at least one PTM, a ULM′ or a VLM′ or a CLM′ or a ILM′ or a MLM′        to the other end of the linker;    -   X¹, X² of Formula ULM-a are each independently selected from the        group of a bond, 0, NR^(Y3), CR^(Y3)R^(Y4), C═O, C═S, SO, and        SO₂;    -   R^(Y3), R^(Y4) of Formula ULM-a are each independently selected        from the group of H, linear or branched C₁₋₆ alkyl, optionally        substituted by 1 or more halo, optionally substituted C₁₋₆        alkoxyl (e.g., optionally substituted by 0-3R^(P) groups);    -   R^(P) of Formula ULM-a is 0, 1, 2, or 3 groups each        independently selected from the group H, halo, —OH, C₁₋₃ alkyl,        C═O;    -   W³ of Formula ULM-a is selected from the group of an optionally        substituted -T-N(R^(1a)R^(1b))X³, optionally substituted        -T-N(R^(1a)R^(1b)), optionally substituted -T-Aryl, an        optionally substituted -T-Heteroaryl, an optionally substituted        T-biheteroaryl, an optionally substituted -T-Heterocycle, an        optionally substituted -T-biheterocycle, an optionally        substituted —NR¹-T-Aryl, an optionally substituted        —NR¹-T-Heteroaryl or an optionally substituted        —NR¹-T-Heterocycle;    -   X³ of Formula ULM-a is C═O, R¹, R^(1a), R^(1b);    -   each of R¹, R^(1a), R^(1b) is independently selected from the        group consisting of H, linear or branched C₁-C₆ alkyl group        optionally substituted by 1 or more halo or —OH groups,        R^(Y3)C═O, R^(Y3)C═S, R^(Y3)SO, R^(Y3)SO₂, N(R^(Y3)R^(Y4))C═O,        N(R^(Y3)R^(Y4))C═S, N(R^(Y3)R^(Y4))SO, and N(R^(Y3)R^(Y4))SO₂;    -   T of Formula ULM-a is covalently bonded to X¹ and is selected        from the group of an optionally substituted alkyl, —(CH₂)_(n)—        group, wherein each one of the methylene groups is optionally        substituted with one or two substituents selected from the group        of halogen, methyl, a linear or branched C₁-C₆ alkyl group        optionally substituted by 1 or more halogen or —OH groups or an        amino acid side chain optionally substituted;    -   W⁴ of Formula ULM-a is an optionally substituted —NR1-T-Aryl, an        optionally substituted —NR1-T-Heteroaryl group or an optionally        substituted —NR1-T-Heterocycle, where —NR¹ is covalently bonded        to X² and R¹ is H or CH₃, preferably H.

In any of the embodiments described herein, T is selected from the groupof an optionally substituted alkyl, —(CH₂)_(n)— group, wherein each oneof the methylene groups is optionally substituted with one or twosubstituents selected from the group of halogen, methyl, a linear orbranched C₁-C₆ alkyl group optionally substituted by 1 or more halogenor —OH groups or an amino acid side chain optionally substituted; and

-   -   n is 0 to 6, often 0, 1, 2, or 3, preferably 0 or 1.

In certain embodiments W⁴ of Formula ULM-a is

wherein

-   -   R_(14a), R_(14b), are each independently selected from the group        of H, haloalkyl, or optionally substituted alkyl.

In any of the embodiments, W⁵ of Formula ULM-a is selected from thegroup of a phenyl or a 5-10 membered heteroaryl,

-   -   R₁₅ of Formula ULM-a is selected from the group of H, halogen,        CN, OH, NO₂, N R_(14a)R_(14b), OR_(14a), CONR_(14a)R_(14b),        NR_(14a)COR_(14b), SO₂NR_(14a)R_(14b), NR_(14a) SO₂R_(14b),        optionally substituted alkyl, optionally substituted haloalkyl,        optionally substituted haloalkoxy; aryl, heteroaryl, cycloalkyl,        or cycloheteroalkyl (each optionally substituted);    -   In additional embodiments, W⁴ substituents for use in the        present disclosure also include specifically (and without        limitation to the specific compound disclosed) the W⁴        substituents which are found in the identified compounds        disclosed herein. Each of these W⁴ substituents may be used in        conjunction with any number of W³ substituents which are also        disclosed herein.

In certain additional embodiments, ULM-a, is optionally substituted by1-3R^(P) groups in the pyrrolidine moiety. Each R^(P) is independentlyH, halo, —OH, C1-3alkyl.

In any of the embodiments described herein, the W³, W⁴ of Formula ULM-acan independently be covalently coupled to a linker which is attachedone or more PTM groups.

and wherein the dashed line indicates the site of attachment of at leastone PTM, another ULM (ULM′) or a chemical linker moiety coupling atleast one PTM or a ULM′ or both to ULM.

In certain embodiments, ULM is VHL and is represented by the structure:

wherein:

-   -   W³ of Formula ULM-b is selected from the group of an optionally        substituted aryl, optionally substituted heteroaryl, or

-   -   R₉ and R₁₀ of Formula ULM-b are independently hydrogen,        optionally substituted alkyl, optionally substituted cycloalkyl,        optionally substituted hydroxyalkyl, optionally substituted        heteroaryl, or haloalkyl, or R₉, R₁₀, and the carbon atom to        which they are attached form an optionally substituted        cycloalkyl;    -   R₁₁ of Formula ULM-b is selected from the group of an optionally        substituted heterocyclic, optionally substituted alkoxy,        optionally substituted heteroaryl, optionally substituted aryl,

-   -   R₁₂ of Formula ULM-b is selected from the group of H or        optionally substituted alkyl,    -   R₁₃ of Formula ULM-b is selected from the group of H, optionally        substituted alkyl, optionally substituted alkylcarbonyl,        optionally substituted (cycloalkyl)alkylcarbonyl, optionally        substituted aralkylcarbonyl, optionally substituted        arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or        optionally substituted aralkyl;    -   R_(14a), R_(14b) of Formula ULM-b, are each independently        selected from the group of H, haloalkyl, or optionally        substituted alkyl;    -   W⁵ of Formula ULM-b is selected from the group of a phenyl or a        5-10 membered heteroaryl,    -   R₁₅ of Formula ULM-b is selected from the group of H, halogen,        CN, OH, NO₂, N R_(14a)R_(14b), OR_(14a), CONR_(14a)R_(14b),        NR_(14a)COR_(14b), SO₂NR_(14a)R_(14b), NR_(14a) SO₂R_(14b),        optionally substituted alkyl, optionally substituted haloalkyl,        optionally substituted haloalkoxy; aryl, heteroaryl, cycloalkyl,        or cycloheteroalkyl (optionally substituted);    -   R₁₆ of Formula ULM-b is independently selected from the group of        halo, optionally substituted alkyl, optionally substituted        haloalkyl, hydroxy, or optionally substituted haloalkoxy;    -   o of Formula ULM-b is 0, 1, 2, 3, or 4;    -   R₁₈ of Formula ULM-b is independently selected from the group of        H, halo, optionally substituted alkoxy, cyano, optionally        substituted alkyl, haloalkyl, haloalkoxy or a linker; and    -   p of Formula ULM-b is 0, 1, 2, 3, or 4, and wherein the dashed        line indicates the site of attachment of at least one PTM,        another ULM (ULM′) or a chemical linker moiety coupling at least        one PTM or a ULM′ or both to ULM.

In certain embodiments, R₁₅ of Formula ULM-b is

wherein R₁₇ is H, halo, optionally substituted C₃₋₆cycloalkyl,optionally substituted C₁₋₆alkyl, optionally substituted C₁₋₆alkenyl,and C₁₋₆haloalkyl; and Xa is S or O.

In certain embodiments, R₁₇ of Formula ULM-b is selected from the groupmethyl, ethyl, isopropyl, and cyclopropyl.

In certain additional embodiments, R₁₅ of Formula ULM-b is selected fromthe group consisting of:

In certain embodiments, R₁₁ of Formula ULM-b is selected from the groupconsisting of:

In certain embodiments, ULM has a chemical structure selected from thegroup of:

wherein:

-   -   R₁ of Formulas ULM-c, ULM-d, and ULM-e is H, ethyl, isopropyl,        tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or        cyclohexyl; optionally substituted alkyl, optionally substituted        hydroxyalkyl, optionally substituted heteroaryl, or haloalkyl;    -   R_(14a) of Formulas ULM-c, ULM-d, and ULM-e is H, haloalkyl,        optionally substituted alkyl, methyl, fluoromethyl,        hydroxymethyl, ethyl, isopropyl, or cyclopropyl;    -   R₁₅ of Formulas ULM-c, ULM-d, and ULM-e is selected from the        group consisting of H, halogen, CN, OH, NO₂, optionally        substituted heteroaryl, optionally substituted aryl; optionally        substituted alkyl, optionally substituted haloalkyl, optionally        substituted haloalkoxy, cycloalkyl, or cycloheteroalkyl (each        optionally substituted);    -   X of Formulas ULM-c, ULM-d, and ULM-e is C, CH₂, or C═O    -   R₃ of Formulas ULM-c, ULM-d, and ULM-e is absent or an        optionally substituted 5 or 6 membered heteroaryl; and    -   wherein the dashed line indicates the site of attachment of at        least one PTM, another ULM (ULM′) or a chemical linker moiety        coupling at least one PTM or a ULM′ or both to ULM.

In certain embodiments, ULM comprises a group according to the chemicalstructure:

wherein:

-   -   R_(14a) of Formula ULM-f is H, haloalkyl, optionally substituted        alkyl, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl, or        cyclopropyl;    -   R₉ of Formula ULM-f is H;    -   R₁₀ of Formula ULM-f is H, ethyl, isopropyl, tert-butyl,        sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;    -   R₁₁ of Formula ULM-f is

or optionally substituted heteroaryl;

-   -   p of Formula ULM-f is 0, 1, 2, 3, or 4;    -   each R₁₈ of Formula ULM-f is independently halo, optionally        substituted alkoxy, cyano, optionally substituted alkyl,        haloalkyl, haloalkoxy or a linker;    -   R₁₂ of Formula ULM-f is H, C═O;    -   R₁₃ of Formula ULM-f is H, optionally substituted alkyl,        optionally substituted alkylcarbonyl, optionally substituted        (cycloalkyl)alkylcarbonyl, optionally substituted        aralkylcarbonyl, optionally substituted arylcarbonyl, optionally        substituted (heterocyclyl)carbonyl, or optionally substituted        aralkyl,    -   R₁₅ of Formula ULM-f is selected from the group consisting of H,        halogen, Cl, CN, OH, NO₂, optionally substituted heteroaryl,        optionally substituted aryl;

-   -   and    -   wherein the dashed line of Formula ULM-f indicates the site of        attachment of at least one PTM, another ULM (ULM′) or a chemical        linker moiety coupling at least one PTM or a ULM′ or both to        ULM.

In certain embodiments, the ULM is selected from the followingstructures:

where n is 0 or 1.

In certain embodiments, the ULM is selected from the followingstructures:

-   -   wherein, the phenyl ring in ULM-al through ULM -a15, ULM-b1        through ULM-b12, ULM-c1 through ULM-c15 and ULM-d1 through        ULM-d9 is optionally substituted with fluorine, lower alkyl and        alkoxy groups, and wherein the dashed line indicates the site of        attachment of at least one PTM, another ULM (ULM′) or a chemical        linker moiety coupling at least one PTM or a ULM′ or both to        ULM-a.

In one embodiment, the phenyl ring in ULM-al through ULM-a15, ULM-b1through ULM-b12, ULM-c1 through ULM-c15 and ULM-d1 through ULM-d9 can befunctionalized as the ester to make it a part of the prodrug.

In certain embodiments, the hydroxyl group on the pyrrolidine ring ofULM-al through ULM-a15, ULM-b1 through ULM-b12, ULM-c1 through ULM-c15and ULM-d1 through ULM-d9, respectively, comprises an ester-linkedprodrug moiety.

In any of the aspects or embodiments described herein, the ULM and wherepresent, ULM′, are each independently a group according to the chemicalstructure:

wherein:

-   -   R^(1′) of ULM-g is an optionally substituted C₁-C₆ alkyl group,        an optionally substituted —(CH₂)_(n)OH, an optionally        substituted —(CH₂)_(n)SH, an optionally substituted        (CH₂)_(n)—O—(C₁-C₆)alkyl group, an optionally substituted        (CH₂)_(n)—WCOCW-(C₀-C₆)alkyl group containing an epoxide moiety        WCOCW where each W is independently H or a C₁-C₃ alkyl group, an        optionally substituted —(CH₂)_(n)COOH, an optionally substituted        —(CH₂)_(n)C(O)—(C₁-C₆ alkyl), an optionally substituted        —(CH₂)_(n)NHC(O)—R₁, an optionally substituted        —(CH₂)_(n)C(O)—NR₁R₂, an optionally substituted        —(CH₂)_(n)OC(O)—NR₁R₂, —(CH₂O)_(n)H, an optionally substituted        —(CH₂)_(n)OC(O)—(C₁-C₆ alkyl), an optionally substituted        —(CH₂)_(n)C(O)—O—(C₁-C₆ alkyl), an optionally substituted        —(CH₂O)_(n)COOH, an optionally substituted —(OCH₂)_(n)O—(C₁-C₆        alkyl), an optionally substituted —(CH₂O)_(n)C(O)—(C₁-C₆ alkyl),        an optionally substituted —(OCH₂)_(n)NHC(O)—R₁, an optionally        substituted —(CH₂O)_(n)C(O)—NR₁R₂, —(CH₂CH₂O)_(n)H, an        optionally substituted —(CH₂CH₂O)_(n)COOH, an optionally        substituted —(OCH₂CH₂)_(n)O—(C₁-C₆ alkyl), an optionally        substituted —(CH₂CH₂O)_(n)C(O)—(C₁-C₆ alkyl), an optionally        substituted —(OCH₂CH₂)_(n)NHC(O)—R₁, an optionally substituted        —(CH₂CH₂O)_(n)C(O)—NR₁R₂, an optionally substituted —SO₂R_(S),        an optionally substituted S(O)R_(S), NO₂, CN or halogen (F, Cl,        Br, I, preferably F or Cl);    -   R₁ and R₂ of ULM-g are each independently H or a C₁-C₆ alkyl        group which may be optionally substituted with one or two        hydroxyl groups or up to three halogen groups (preferably        fluorine);    -   R_(S) of ULM-g is a C₁-C₆ alkyl group, an optionally substituted        aryl, heteroaryl or heterocycle group or a —(CH₂)_(m)NR₁R₂        group;    -   X and X′ of ULM-g are each independently C═O, C═S, —S(O), S(O)₂,        (preferably X and X′ are both C═O);    -   R^(2′) of ULM-g is an optionally substituted        —(CH₂)_(n)—(C═O)_(u)(NR¹)_(v)(SO₂)_(w)alkyl group, an optionally        substituted —(CH₂)_(n),        —(C═O)_(u)(NR¹)_(v)(SO₂)_(w)NR_(1N)R_(2N) group, an optionally        substituted —(CH₂)_(n)—(C═O)_(u)(NR¹)_(v)(SO₂)_(w)-Aryl, an        optionally substituted        —(CH₂)_(n)—(C═O)_(u)(NR₁)_(v)(SO₂)_(w)-Heteroaryl, an optionally        substituted —(CH₂)_(n)—(C═O)_(v)NR₁(SO₂)_(w)-Heterocycle, an        optionally substituted        —NR₁—(CH₂)_(n)—C(O)_(u)(NR₁)_(v)(SO₂)_(w)-alkyl, an optionally        substituted        —NR¹—(CH₂)_(n)—C(O)_(u)(NR₁)_(v)(SO₂)_(w)—NR_(1N)R_(2N), an        optionally substituted        —NR¹—(CH₂)_(n)—C(O)_(u)(NR₁)_(v)(SO₂)_(w)—NR₁C(O)R_(1N), an        optionally substituted        —NR¹—(CH₂)_(n)—(C═O)_(u)(NR₁)_(v)(SO₂)_(w)-Aryl, an optionally        substituted        —NR¹—(CH₂)_(n)—(C═O)_(u)(NR₁)_(v)(SO₂)_(w)-Heteroaryl or an        optionally substituted        —NR¹—(CH₂)_(n)—(C═O)_(v)NR₁(SO₂)_(w)-Heterocycle, an optionally        substituted —X^(R2′)-alkyl group; an optionally substituted        —X^(R2′)-Aryl group; an optionally substituted        —X^(R2′)-Heteroaryl group; an optionally substituted        —X^(R2′)-Heterocycle group; an optionally substituted;    -   R^(3′) of ULM-g is an optionally substituted alkyl, an        optionally substituted        —(CH₂)_(n)—(O)_(u)(NR₁)_(v)(SO₂)_(w)-alkyl, an optionally        substituted —(CH₂)_(n)—C(O)_(u)(NR₁)_(v)(SO₂)_(w)—NR_(1N)R_(2N),        an optionally substituted        —(CH₂)_(n)—C(O)_(u)(NR₁)_(v)(SO₂)_(w)—NR₁C(O)R_(1N), an        optionally substituted        —(CH₂)_(n)—C(O)_(u)(NR₁)_(v)(SO₂)_(w)—C(O)NR₁R₂, an optionally        substituted —(CH₂)_(n)—C(O)_(u)(NR₁)_(v)(SO₂)_(w)-Aryl, an        optionally substituted        —(CH₂)_(n)—C(O)_(u)(NR₁)_(v)(SO₂)_(w)-Heteroaryl, an optionally        substituted —(CH₂)_(n)—C(O)_(u)(NR₁)_(v)(SO₂)_(w)-Heterocycle,        an optionally substituted        —NR¹—(CH₂)_(n)—C(O)_(u)(NR₁)_(v)(SO₂)_(w)-alkyl, an optionally        substituted        —NR¹—(CH₂)_(n)—C(O)_(u)(NR₁)_(v)(SO₂)_(w)—NR_(1N)R_(2N), an        optionally substituted        —NR¹—(CH₂)_(n)—C(O)_(u)(NR₁)_(v)(SO₂)_(w)—NR₁C(O)R₁N, an        optionally substituted        —NR¹—(CH₂)_(n)—C(O)_(u)(NR₁)_(v)(SO₂)_(w)-Aryl, an optionally        substituted        —NR₁—(CH₂)_(n)—C(O)_(u)(NR₁)_(v)(SO₂)_(w)-Heteroaryl, an        optionally substituted        —NR¹—(CH₂)_(n)—C(O)_(u)(NR₁)_(v)(SO₂)_(w)-Heterocycle, an        optionally substituted        —O—(CH₂)_(n)—(C═O)_(u)(NR¹)_(v)(SO₂)_(w)-alkyl, an optionally        substituted        —O—(CH₂)_(n)—(C═O)_(u)(NR₁)_(v)(SO₂)_(w)—NR_(1N)R_(2N), an        optionally substituted        —O—(CH₂)_(n)—(C═O)_(u)(NR¹)_(v)(SO₂)_(w)—NR₁C(O)R_(1N), an        optionally substituted        —O—(CH₂)_(n)—(C═O)_(u)(NR₁)_(v)(SO₂)_(w)-Aryl, an optionally        substituted —O—(CH₂)_(n)—(C═O)_(u)(NR₁)_(v)(SO₂)_(w)-Heteroaryl        or an optionally substituted        —O—(CH₂)_(n)—(C═O)_(u)(NR₁)_(v)(SO₂)_(w)-Heterocycle;        —(CH₂)_(n)—(V)_(n′)—(CH₂)_(n)—(V)_(n′)-alkyl group, an        optionally substituted        —(CH₂)_(n)—(V)_(n′)—(CH₂)_(n)—(V)_(n′)-Aryl group, an optionally        substituted —(CH₂)_(n)—(V)_(n′)—(CH₂)_(n)—(V)_(n′)-Heteroaryl        group, an optionally substituted        —(CH₂)_(n)—(V)_(n′)—(CH₂)_(n)—(V)_(n′)-Heterocycle group, an        optionally substituted        —(CH₂)_(n)—N(R_(1′))(C═O)_(m′)—(V)_(n′)-alkyl group, an        optionally substituted        —(CH₂)_(n)—N(R_(1′))(C═O)_(m′)—(V)_(n′)-Aryl group, an        optionally substituted        —(CH₂)_(n)—N(R_(1′))(C═O)_(m′)—(V)_(n′)-Heteroaryl group, an        optionally substituted        —(CH₂)_(n)—N(R_(1′))(C═O)_(m′)—(V)_(n′)-Heterocycle group, an        optionally substituted —X^(R3′)-alkyl group; an optionally        substituted —X^(R3′)-Aryl group; an optionally substituted        —X^(R3′)-Heteroaryl group; an optionally substituted        —X^(R3′)-Heterocycle group; an optionally substituted;    -   R_(1N) and R_(2N) of ULM-g are each independently H, C₁-C₆ alkyl        which is optionally substituted with one or two hydroxyl groups        and up to three halogen groups or an optionally substituted        —(CH₂)_(n)-Aryl, —(CH₂)_(n)-Heteroaryl or —(CH₂)_(n)-Heterocycle        group;    -   V of ULM-g is O, S or NR₁;    -   R₁ of ULM-g is the same as above;    -   R¹ and R_(1′) of ULM-g are each independently H or a C₁-C₃ alkyl        group;    -   X^(R2′) and X^(R3′) of ULM-g are each independently an        optionally substituted —CH₂)_(n)—,        —CH₂)_(n)—CH(X_(v))═CH(X_(v))— (cis or trans), —CH₂)_(n)—CH≡CH—,        —(CH₂CH₂O)_(n)— or a C₃-C₆ cycloalkyl group, where X_(v) is H, a        halo or a C₁-C₃ alkyl group which is optionally substituted;    -   each m of ULM-g is independently 0, 1, 2, 3, 4, 5, 6;    -   each m′ of ULM-g is independently 0 or 1;    -   each n of ULM-g is independently 0, 1, 2, 3, 4, 5, 6;    -   each n′ of ULM-g is independently 0 or 1;    -   each u of ULM-g is independently 0 or 1;    -   each v of ULM-g is independently 0 or 1;    -   each w of ULM-g is independently 0 or 1; and    -   any one or more of R^(1′), R^(2′), R^(3′), X and X′ of ULM-g is        optionally modified to be covalently bonded to the PTM group        through a linker group when PTM is not ULM′, or when PTM is        ULM′, any one or more of R^(1′), R^(2′), R^(3′), X and X′ of        each of ULM and ULM′ are optionally modified to be covalently        bonded to each other directly or through a linker group, or a        pharmaceutically acceptable salt, stereoisomer, solvate or        polymorph thereof.

In any of the aspects or embodiments described herein, the ULM and whenpresent, ULM′, are each independently a group according to the chemicalstructure:

wherein:

-   -   each of R^(1′), R^(2′) and R^(3′) of ULM-h are the same as above        and X is C═O, C═S, —S(O) group or a S(O)₂ group, more preferably        a C═O group, and    -   any one or more of R^(1′), R^(2′) and R^(3′) of ULM-h are        optionally modified to bind a linker group to which is further        covalently bonded to the PTM group when PTM is not ULM′, or when        PTM is ULM′, any one or more of R^(1′), R^(2′), R^(3′) of each        of ULM and ULM′ are optionally modified to be covalently bonded        to each other directly or through a linker group, or    -   a pharmaceutically acceptable salt, enantiomer, diastereomer,        solvate or polymorph thereof.

In any of the aspects or embodiments described herein, the ULM, and whenpresent, ULM′, are each independently according to the chemicalstructure:

wherein:

-   -   any one or more of R^(1′), R^(2′) and R^(3′) of ULM-I are        optionally modified to bind a linker group to which is further        covalently bonded to the PTM group when PTM is not ULM′, or when        PTM is ULM′, any one or more of R^(1′), R^(2′), R^(3′) of each        of ULM and ULM′ are optionally modified to be covalently bonded        to each other directly or through a linker group, or    -   a pharmaceutically acceptable salt, enantiomer, diastereomer,        solvate or polymorph thereof.

In further preferred aspects of the disclosure, R^(1′) of ULM-g throughULM-i is preferably a hydroxyl group or a group which may be metabolizedto a hydroxyl or carboxylic group, such that the compound represents aprodrug form of an active compound. Exemplary preferred R^(1′) groupsinclude, for example, —(CH₂)_(n)OH, (CH₂)_(n)—O—(C₁-C₆)alkyl group,—(CH₂)_(n)COOH, —(CH₂O)_(n)H, an optionally substituted—(CH₂)_(n)OC(O)—(C₁-C₆ alkyl), or an optionally substituted—(CH₂)_(n)C(O)—O—(C₁-C₆ alkyl), wherein n is 0 or 1. Where R^(1′) is orcontains a carboxylic acid group, a hydroxyl group or an amine group,the hydroxyl group, carboxylic acid group or amine (each of which may beoptionally substituted), may be further chemically modified to provide acovalent link to a linker group to which the PTM group (including a ULM′group) is bonded;

-   -   X and X′, where present, of ULM-g and ULM-h are preferably a        C═O, C═S, —S(O) group or a S(O)₂ group, more preferably a C═O        group;    -   R^(2′) of ULM-g through ULM-i is preferably an optionally        substituted —NR¹-T-Aryl, an optionally substituted        —NR¹-T-Heteroaryl group or an optionally substituted        —NR¹-T-Heterocycle, where R¹ is H or CH₃, preferably H and T is        an optionally substituted —(CH₂)_(n)— group, wherein each one of        the methylene groups may be optionally substituted with one or        two substituents, preferably selected from halogen, an amino        acid sidechain as otherwise described herein or a C₁-C₃ alkyl        group, preferably one or two methyl groups, which may be        optionally substituted; and n is 0 to 6, often 0, 1, 2 or 3,        preferably 0 or 1. Alternatively, T may also be a —(CH₂O)_(n)—        group, a —(OCH₂)_(n)— group, a —(CH₂CH₂O)_(n)— group, a        —(OCH₂CH₂)_(n)— group, all of which groups are optionally        substituted.

Preferred Aryl groups for R^(2′) of ULM-g through ULM-i includeoptionally substituted phenyl or naphthyl groups, preferably phenylgroups, wherein the phenyl or naphthyl group is connected to a PTM(including a ULM′ group) with a linker group and/or optionallysubstituted with a halogen (preferably F or Cl), an amine, monoalkyl- ordialkyl amine (preferably, dimethylamine), F, Cl, OH, COOH, C₁-C₆ alkyl,preferably CH₃, CF₃, OMe, OCF₃, NO₂, or CN group (each of which may besubstituted in ortho-, meta- and/or para-positions of the phenyl ring,preferably para-), an optionally substituted phenyl group (the phenylgroup itself is optionally connected to a PTM group, including a ULM′,with a linker group), and/or optionally substituted with at least one ofF, Cl, OH, COOH, CH₃, CF₃, OMe, OCF₃, NO₂, or CN group (in ortho-, meta-and/or para-positions of the phenyl ring, preferably para-), a naphthylgroup, which may be optionally substituted, an optionally substitutedheteroaryl, preferably an optionally substituted isoxazole including amethylsubstituted isoxazole, an optionally substituted oxazole includinga methylsubstituted oxazole, an optionally substituted thiazoleincluding a methyl substituted thiazole, an optionally substitutedisothiazole including a methyl substituted isothiazole, an optionallysubstituted pyrrole including a methylsubstituted pyrrole, an optionallysubstituted imidazole including a methylimidazole, an optionallysubstituted benzimidazole or methoxybenzylimidazole, an optionallysubstituted oximidazole or methyloximidazole, an optionally substituteddiazole group, including a methyldiazole group, an optionallysubstituted triazole group, including a methylsubstituted triazolegroup, an optionally substituted pyridine group, including a halo-(preferably, F) or methylsubstitutedpyridine group or an oxapyridinegroup (where the pyridine group is linked to the phenyl group by anoxygen), an optionally substituted furan, an optionally substitutedbenzofuran, an optionally substituted dihydrobenzofuran, an optionallysubstituted indole, indolizine or azaindolizine (2, 3, or4-azaindolizine), an optionally substituted quinoline, an optionallysubstituted group according to the chemical structure:

wherein:

-   -   S^(c) of ULM-g through ULM-i is CHR^(SS), NR^(URE), or O;    -   R^(HET) of ULM-g through ULM-i is H, CN, NO₂, halo (preferably        Cl or F), optionally substituted C₁-C₆ alkyl (preferably        substituted with one or two hydroxyl groups or up to three halo        groups (e.g. CF₃), optionally substituted O(C₁-C₆ alkyl)        (preferably substituted with one or two hydroxyl groups or up to        three halo groups) or an optionally substituted acetylenic group        —C≡C—R_(a) where R_(a) is H or a C₁-C₆ alkyl group (preferably        C₁-C₃ alkyl);    -   R^(SS) of ULM-g through ULM-i is H, CN, NO₂, halo (preferably F        or Cl), optionally substituted C₁-C₆ alkyl (preferably        substituted with one or two hydroxyl groups or up to three halo        groups), optionally substituted O—(C₁-C₆ alkyl) (preferably        substituted with one or two hydroxyl groups or up to three halo        groups) or an optionally substituted —C(O)(C₁-C₆alkyl)        (preferably substituted with one or two hydroxyl groups or up to        three halo groups);    -   R^(URE) of ULM-g through ULM-i is H, a C₁-C₆ alkyl (preferably H        or C₁-C₃ alkyl) or a —C(O)(C₁-C₆ alkyl) each of which groups is        optionally substituted with one or two hydroxyl groups or up to        three halogen, preferably fluorine groups, or an optionally        substituted phenyl group, an optionally substituted heteroaryl,        or an optionally substituted heterocycle, preferably for example        piperidine, morpholine, pyrrolidine, tetrahydrofuran);    -   R^(PRO) of ULM-g through ULM-i is H, optionally substituted        C₁-C₆ alkyl or an optionally substituted aryl (phenyl or        napthyl), heteroaryl or heterocyclic group selected from the        group consisting of oxazole, isoxazole, thiazole, isothiazole,        imidazole, diazole, oximidazole, pyrrole, pyrollidine, furan,        dihydrofuran, tetrahydrofuran, thiene, dihydrothiene,        tetrahydrothiene, pyridine, piperidine, piperazine, morpholine,        quinoline, (each preferably substituted with a C₁-C₃ alkyl        group, preferably methyl or a halo group, preferably F or Cl),        benzofuran, indole, indolizine, azaindolizine;    -   R^(PRO1) and R^(PRO2 of ULM-g through ULM-i) are each        independently H, an optionally substituted C₁-C₃ alkyl group or        together form a keto group; and    -   each n of ULM-g through ULM-i is independently 0, 1, 2, 3, 4, 5,        or 6 (preferably 0 or 1), or an optionally substituted        heterocycle, preferably tetrahydrofuran, tetrahydrothiene,        piperidine, piperazine or morpholine (each of which groups when        substituted, are preferably substituted with a methyl or halo        (F, Br, Cl), each of which groups may be optionally        attached/coupled to a PTM group (including a ULM′ group) via a        linker group.

In certain preferred aspects,

of ULM-g through ULM-i is

where R^(PRO) and n of ULM-g through ULM-i are the same as above.

Preferred heteroaryl groups for R^(2′) of ULM-g through ULM-i include anoptionally substituted quinoline (which may be attached to thepharmacophore or substituted on any carbon atom within the quinolinering), an optionally substituted indole, an optionally substitutedindolizine, an optionally substituted azaindolizine, an optionallysubstituted benzofuran, including an optionally substituted benzofuran,an optionally substituted isoxazole, an optionally substituted thiazole,an optionally substituted isothiazole, an optionally substitutedthiophene, an optionally substituted pyridine (2-, 3, or 4-pyridine), anoptionally substituted imidazole, an optionally substituted pyrrole, anoptionally substituted diazole, an optionally substituted triazole, atetrazole, an optionally substituted oximidazole, or a group accordingto the chemical structure:

wherein:

-   -   S^(c) of ULM-g through ULM-i is CHR^(SS), NR^(U)R^(E), or O;    -   R^(HET) of ULM-g through ULM-i is H, CN, NO₂, halo (preferably        Cl or F), optionally substituted C₁-C₆ alkyl (preferably        substituted with one or two hydroxyl groups or up to three halo        groups (e.g. CF₃), optionally substituted O(C₁-C₆ alkyl)        (preferably substituted with one or two hydroxyl groups or up to        three halo groups) or an optionally substituted acetylenic group        —C≡C—R_(a) where R_(a) of ULM-g through ULM-i is H or a C₁-C₆        alkyl group (preferably C₁-C₃ alkyl);    -   R^(SS) of ULM-g through ULM-i is H, CN, NO₂, halo (preferably F        or Cl), optionally substituted C₁-C₆ alkyl (preferably        substituted with one or two hydroxyl groups or up to three halo        groups), optionally substituted O—(C₁-C₆ alkyl) (preferably        substituted with one or two hydroxyl groups or up to three halo        groups) or an optionally substituted —C(O)(C₁-C₆alkyl)        (preferably substituted with one or two hydroxyl groups or up to        three halo groups);    -   R^(URE) of ULM-g through ULM-i is H, a C₁-C₆ alkyl (preferably H        or C₁-C₃ alkyl) or a —C(O)(C₁-C₆ alkyl), each of which groups is        optionally substituted with one or two hydroxyl groups or up to        three halogen, preferably fluorine groups, or an optionally        substituted heterocycle, for example piperidine, morpholine,        pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine,        piperazine, each of which is optionally substituted, and    -   Y^(C) of ULM-g through ULM-i is N or C—R^(YC), where R^(YC) is        H, OH, CN, NO₂, halo (preferably Cl or F), optionally        substituted C₁-C₆ alkyl (preferably substituted with one or two        hydroxyl groups or up to three halo groups (e.g. CF₃),        optionally substituted O(C₁-C₆ alkyl) (preferably substituted        with one or two hydroxyl groups or up to three halo groups) or        an optionally substituted acetylenic group —C≡C—R_(a) where        R_(a) is H or a C₁-C₆ alkyl group (preferably C₁-C₃ alkyl), each        of which groups may be optionally connected/coupled to a PTM        group (including a ULM′ group) via a linker group.

Preferred heterocycle groups for R^(2′) of ULM-g through ULM-i includetetrahydrofuran, tetrahydrothiene, tetrahydroquinoline, piperidine,piperazine, pyrrollidine, morpholine, oxane or thiane, each of whichgroups may be optionally substituted, or a group according to thechemical structure:

-   -   preferably, a

group,wherein:

-   -   R^(PRO) of ULM-g through ULM-i is H, optionally substituted        C₁-C₆ alkyl or an optionally substituted aryl, heteroaryl or        heterocyclic group;    -   R^(PRO1) and R^(PRO2) of ULM-g through ULM-i are each        independently H, an optionally substituted C₁-C₃ alkyl group or        together form a keto group and    -   each n of ULM-g through ULM-i is independently 0, 1, 2, 3, 4, 5,        or 6 (often 0 or 1), each of which groups may be optionally        connected/coupled to a PTM group (including a ULM′ group) via a        linker group.

Preferred R^(2′) substituents of ULM-g through ULM-i also includespecifically (and without limitation to the specific compound disclosed)the R^(2′) substituents which are found in the identified compoundsdisclosed herein (which includes the specific compounds which aredisclosed in the present specification, and the figures which areattached hereto). Each of these R^(2′) substituents may be used inconjunction with any number of R^(3′) substituents which are alsodisclosed herein.

-   -   R^(3′) of ULM-g through ULM-i is preferably an optionally        substituted -T-Aryl, an optionally substituted-T-Heteroaryl, an        optionally substituted -T-Heterocycle, an optionally        substituted-NR¹-T-Aryl, an optionally substituted        —NR¹-T-Heteroaryl or an optionally        substituted-NR¹-T-Heterocycle, where R¹ is H or a C₁-C₃ alkyl        group, preferably H or CH₃, T is an optionally substituted        —(CH₂)_(n)— group, wherein each one of the methylene groups may        be optionally substituted with one or two substituents,        preferably selected from halogen, a C₁-C₃ alkyl group or the        sidechain of an amino acid as otherwise described herein,        preferably methyl, which may be optionally substituted; and n is        0 to 6, often 0, 1, 2, or 3 preferably 0 or 1. Alternatively, T        may also be a —(CH₂O)_(n)— group, a —(OCH₂)_(n)— group, a        —(CH₂CH₂O)_(n)— group, a —(OCH₂CH₂)_(n)— group, each of which        groups is optionally substituted.

Preferred aryl groups for R^(3′) of ULM-g through ULM-i includeoptionally substituted phenyl or naphthyl groups, preferably phenylgroups, wherein the phenyl or naphthyl group is optionallyconnected/coupled to a PTM group (including a ULM′ group) via a linkergroup and/or optionally substituted with a halogen (preferably F or Cl),an amine, monoalkyl- or dialkyl amine (preferably, dimethylamine), anamido group (preferably a —(CH₂)_(m)—NR₁C(O)R₂ group where m, R₁ and R₂are the same as above), a halo (often F or Cl), OH, CH₃, CF₃, OMe, OCF₃,NO₂, CN or a S(O)₂R_(S) group (R_(S) is a C₁-C₆ alkyl group, anoptionally substituted aryl, heteroaryl or heterocycle group or a—(CH₂)_(m)NR₁R₂ group), each of which may be substituted in ortho-,meta- and/or para-positions of the phenyl ring, preferably para-), or anAryl (preferably phenyl), Heteroaryl or Heterocycle. Preferably saidsubstituent phenyl group is an optionally substituted phenyl group(i.e., the substituent phenyl group itself is preferably substitutedwith at least one of F, Cl, OH, SH, COOH, CH₃, CF₃, OMe, OCF₃, NO₂, CNor a linker group to which is attached a PTM group (including a ULM′group), wherein the substitution occurs in ortho-, meta- and/orpara-positions of the phenyl ring, preferably para-), a naphthyl group,which may be optionally substituted including as described above, anoptionally substituted heteroaryl (preferably an optionally substitutedisoxazole including a methylsubstituted isoxazole, an optionallysubstituted oxazole including a methylsubstituted oxazole, an optionallysubstituted thiazole including a methyl substituted thiazole, anoptionally substituted pyrrole including a methylsubstituted pyrrole, anoptionally substituted imidazole including a methylimidazole, abenzylimidazole or methoxybenzylimidazole, an oximidazole ormethyloximidazole, an optionally substituted diazole group, including amethyldiazole group, an optionally substituted triazole group, includinga methylsubstituted triazole group, a pyridine group, including ahalo-(preferably, F) or methylsubstitutedpyridine group or anoxapyridine group (where the pyridine group is linked to the phenylgroup by an oxygen) or an optionally substituted heterocycle(tetrahydrofuran, tetrahydrothiophene, pyrrolidine, piperidine,morpholine, piperazine, tetrahydroquinoline, oxane or thiane. Each ofthe aryl, heteroaryl or heterocyclic groups may be optionallyconnected/coupled to a PTM group (including a ULM′ group) via a linkergroup.

Preferred Heteroaryl groups for R^(3′) of ULM-g through ULM-i include anoptionally substituted quinoline (which may be attached to thepharmacophore or substituted on any carbon atom within the quinolinering), an optionally substituted indole (including dihydroindole), anoptionally substituted indolizine, an optionally substitutedazaindolizine (2, 3 or 4-azaindolizine) an optionally substitutedbenzimidazole, benzodiazole, benzoxofuran, an optionally substitutedimidazole, an optionally substituted isoxazole, an optionallysubstituted oxazole (preferably methyl substituted), an optionallysubstituted diazole, an optionally substituted triazole, a tetrazole, anoptionally substituted benzofuran, an optionally substituted thiophene,an optionally substituted thiazole (preferably methyl and/or thiolsubstituted), an optionally substituted isothiazole, an optionallysubstituted triazole (preferably a 1,2,3-triazole substituted with amethyl group, a triisopropylsilyl group, an optionally substituted—(CH₂)_(m)—O—C₁-C₆ alkyl group or an optionally substituted—(CH₂)_(m)—C(O)—O—C₁-C₆ alkyl group), an optionally substituted pyridine(2-, 3, or 4-pyridine) or a group according to the chemical structure:

wherein:

-   -   S^(c) of ULM-g through ULM-i is CHR^(SS), NR^(URE), or 0;    -   R^(HET) of ULM-g through ULM-i is H, CN, NO₂, halo (preferably        Cl or F), optionally substituted C₁-C₆ alkyl (preferably        substituted with one or two hydroxyl groups or up to three halo        groups (e.g. CF₃), optionally substituted O(C₁-C₆ alkyl)        (preferably substituted with one or two hydroxyl groups or up to        three halo groups) or an optionally substituted acetylenic group        —C≡C—R_(a) where R_(a) is H or a C₁-C₆ alkyl group (preferably        C₁-C₃ alkyl);    -   R^(SS) of ULM-g through ULM-i is H, CN, NO₂, halo (preferably F        or Cl), optionally substituted C₁-C₆ alkyl (preferably        substituted with one or two hydroxyl groups or up to three halo        groups), optionally substituted O—(C₁-C₆ alkyl) (preferably        substituted with one or two hydroxyl groups or up to three halo        groups) or an optionally substituted —C(O)(C₁-C₆alkyl)        (preferably substituted with one or two hydroxyl groups or up to        three halo groups);    -   R^(URE) of ULM-g through ULM-i is H, a C₁-C₆ alkyl (preferably H        or C₁-C₃ alkyl) or a —C(O)(C₁-C₆ alkyl), each of which groups is        optionally substituted with one or two hydroxyl groups or up to        three halogen, preferably fluorine groups, or an optionally        substituted heterocycle, for example piperidine, morpholine,        pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine,        piperazine, each of which is optionally substituted, and    -   Y^(C) of ULM-g through ULM-i is N or C—R^(YC), where R^(YC) is        H, OH, CN, NO₂, halo (preferably Cl or F), optionally        substituted C₁-C₆ alkyl (preferably substituted with one or two        hydroxyl groups or up to three halo groups (e.g. CF₃),        optionally substituted O(C₁-C₆ alkyl) (preferably substituted        with one or two hydroxyl groups or up to three halo groups) or        an optionally substituted acetylenic group —C≡C—R_(a) where        R_(a) is H or a C₁-C₆ alkyl group (preferably C₁-C₃ alkyl). Each        of said heteroaryl groups may be optionally connected/coupled to        a PTM group (including a ULM′ group) via a linker group.

Preferred heterocycle groups for R³ of ULM-g through ULM-i includetetrahydroquinoline, piperidine, piperazine, pyrrollidine, morpholine,tetrahydrofuran, tetrahydrothiophene, oxane and thiane, each of whichgroups may be optionally substituted or a group according to thechemical structure:

preferably, a

group,wherein:

-   -   R^(PRO) of ULM-g through ULM-i is H, optionally substituted        C₁-C₆ alkyl or an optionally substituted aryl (phenyl or        napthyl), heteroaryl or heterocyclic group selected from the        group consisting of oxazole, isoxazole, thiazole, isothiazole,        imidazole, diazole, oximidazole, pyrrole, pyrollidine, furan,        dihydrofuran, tetrahydrofuran, thiene, dihydrothiene,        tetrahydrothiene, pyridine, piperidine, piperazine, morpholine,        quinoline, (each preferably substituted with a C₁-C₃ alkyl        group, preferably methyl or a halo group, preferably F or Cl),        benzofuran, indole, indolizine, azaindolizine;    -   R^(PRO1) and R^(PRO2) of ULM-g through ULM-i are each        independently H, an optionally substituted C₁-C₃ alkyl group or        together form a keto group, and    -   each n of ULM-g through ULM-i is 0, 1, 2, 3, 4, 5, or 6        (preferably 0 or 1), wherein each of said Heterocycle groups may        be optionally connected/coupled to a PTM group (including a ULM′        group) via a linker group.

Preferred R^(3′) substituents of ULM-g through ULM-i also includespecifically (and without limitation to the specific compound disclosed)the R^(3′) substituents which are found in the identified compoundsdisclosed herein (which includes the specific compounds which aredisclosed in the present specification, and the figures which areattached hereto). Each of these R^(3′) substituents may be used inconjunction with any number of R^(2′) substituents, which are alsodisclosed herein.

In certain alternative preferred embodiments, R^(2′) of ULM-g throughULM-i is an optionally substituted —NR₁—X^(R2′)-alkyl group,—NR₁—X^(R2′)-Aryl group; an optionally substituted —NR₁—X^(R2′)-HET, anoptionally substituted —NR₁—X^(R2′)-Aryl-HET or an optionallysubstituted —NR₁—X^(R2′)-HET-Aryl,

wherein:

-   -   R₁ of ULM-g through ULM-i is H or a C₁-C₃ alkyl group        (preferably H);    -   X^(R2′) of ULM-g through ULM-i is an optionally substituted        —CH₂)_(n)—, —CH₂)_(n)—CH(X_(v))═CH(X_(t))— (cis or trans),        —(CH₂)_(n)—CH—CH—, —(CH₂CH₂O)_(n)— or a C₃-C₆ cycloalkyl group;        and    -   X_(v) of ULM-g through ULM-i is H, a halo or a C₁-C₃ alkyl group        which is optionally substituted with one or two hydroxyl groups        or up to three halogen groups;    -   Alkyl of ULM-g through ULM-i is an optionally substituted C₁-C₁₀        alkyl (preferably a C₁-C₆ alkyl) group (in certain preferred        embodiments, the alkyl group is end-capped with a halo group,        often a Cl or Br);    -   Aryl of ULM-g through ULM-i is an optionally substituted phenyl        or naphthyl group (preferably, a phenyl group); and    -   HET of ULM-g through ULM-i is an optionally substituted oxazole,        isoxazole, thiazole, isothiazole, imidazole, diazole,        oximidazole, pyrrole, pyrollidine, furan, dihydrofuran,        tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene,        pyridine, piperidine, piperazine, morpholine, benzofuran,        indole, indolizine, azaindolizine, quinoline (when substituted,        each preferably substituted with a C₁-C₃ alkyl group, preferably        methyl or a halo group, preferably F or Cl) or a group according        to the chemical structure:

-   -   S^(c) of ULM-g through ULM-i is CHR^(SS), NR^(URE), or O;    -   R^(HET) of ULM-g through ULM-i is H, CN, NO₂, halo (preferably        Cl or F), optionally substituted C₁-C₆ alkyl (preferably        substituted with one or two hydroxyl groups or up to three halo        groups (e.g. CF₃), optionally substituted O(C₁-C₆ alkyl)        (preferably substituted with one or two hydroxyl groups or up to        three halo groups) or an optionally substituted acetylenic group        —C≡C—R_(a) where R_(a) is H or a C₁-C₆ alkyl group (preferably        C₁-C₃ alkyl);    -   R^(SS) of ULM-g through ULM-i is H, CN, NO₂, halo (preferably F        or Cl), optionally substituted C₁-C₆ alkyl (preferably        substituted with one or two hydroxyl groups or up to three halo        groups), optionally substituted O—(C₁-C₆ alkyl) (preferably        substituted with one or two hydroxyl groups or up to three halo        groups) or an optionally substituted —C(O)(C₁-C₆alkyl)        (preferably substituted with one or two hydroxyl groups or up to        three halo groups);    -   R^(URE) of ULM-g through ULM-i is H, a C₁-C₆ alkyl (preferably H        or C₁-C₃ alkyl) or a —C(O)(C₁-C₆ alkyl), each of which groups is        optionally substituted with one or two hydroxyl groups or up to        three halogen, preferably fluorine groups, or an optionally        substituted heterocycle, for example piperidine, morpholine,        pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine,        piperazine, each of which is optionally substituted;    -   Y^(C) of ULM-g through ULM-i is N or C—R^(YC), where R^(YC) is        H, OH, CN, NO₂, halo (preferably Cl or F), optionally        substituted C₁-C₆ alkyl (preferably substituted with one or two        hydroxyl groups or up to three halo groups (e.g. CF₃),        optionally substituted O(C₁-C₆ alkyl) (preferably substituted        with one or two hydroxyl groups or up to three halo groups) or        an optionally substituted acetylenic group —C≡C—R_(a) where        R_(a) is H or a C₁-C₆ alkyl group (preferably C₁-C₃ alkyl);    -   R^(PRO) of ULM-g through ULM-i is H, optionally substituted        C₁-C₆ alkyl or an optionally substituted aryl (phenyl or        napthyl), heteroaryl or heterocyclic group selected from the        group consisting of oxazole, isoxazole, thiazole, isothiazole,        imidazole, diazole, oximidazole, pyrrole, pyrollidine, furan,        dihydrofuran, tetrahydrofuran, thiene, dihydrothiene,        tetrahydrothiene, pyridine, piperidine, piperazine, morpholine,        quinoline, (each preferably substituted with a C₁-C₃ alkyl        group, preferably methyl or a halo group, preferably F or Cl),        benzofuran, indole, indolizine, azaindolizine;    -   R^(PRO1) and R^(PRO2) of ULM-g through ULM-i are each        independently H, an optionally substituted C₁-C₃ alkyl group or        together form a keto group, and    -   each n of ULM-g through ULM-i is independently 0, 1, 2, 3, 4, 5,        or 6 (preferably 0 or 1).

Each of said groups may be optionally connected/coupled to a PTM group(including a ULM′ group) via a linker group.

In certain alternative preferred embodiments of the present disclosure,R^(3′) of ULM-g through ULM-i is an optionally substituted—(CH₂)_(n)—(V)_(n′)—(CH₂)_(n)—(V)_(n′)—R^(S3′) group, an optionallysubstituted-(CH₂)_(n)—N(R_(1′))(C═O)_(m′)—(V)_(n′)—R^(S3′) group, anoptionally substituted —X^(R3′)-alkyl group, an optionally substituted—X^(R3′)-Aryl group; an optionally substituted —X^(R3′)-HET group, anoptionally substituted —X^(R3′)-Aryl-HET group or an optionallysubstituted —X^(R3′)-HET-Aryl group,

wherein:

-   -   R^(S3′) is an optionally substituted alkyl group (C₁-C₁₀,        preferably C₁-C₆ alkyl), an optionally substituted Aryl group or        a HET group;    -   R_(1′) is H or a C₁-C₃ alkyl group (preferably H);    -   V is O, S or NR¹;    -   X^(R3′) is —(CH₂)_(n)—, —(CH₂CH₂O)_(n)—,        —CH₂)_(n)—CH(X_(v))═CH(X_(v))— (cis or trans), —CH₂)_(n)—CH≡CH—,        or a C₃-C₆ cycloalkyl group, all optionally substituted;    -   X_(v) is H, a halo or a C₁-C₃ alkyl group which is optionally        substituted with one or two hydroxyl groups or up to three        halogen groups;    -   Alkyl is an optionally substituted C₁-C₁₀alkyl (preferably a        C₁-C₆ alkyl) group (in certain preferred embodiments, the alkyl        group is end-capped with a halo group, often a Cl or Br);    -   Aryl is an optionally substituted phenyl or napthyl group        (preferably, a phenyl group); and    -   HET is an optionally substituted oxazole, isoxazole, thiazole,        isothiazole, imidazole, diazole, oximidazole, pyrrole,        pyrollidine, furan, dihydrofuran, tetrahydrofuran, thiene,        dihydrothiene, tetrahydrothiene, pyridine, piperidine,        piperazine, morpholine, benzofuran, indole, indolizine,        azaindolizine, quinoline (when substituted, each preferably        substituted with a C₁-C₃ alkyl group, preferably methyl or a        halo group, preferably F or Cl), or a group according to the        chemical structure:

-   -   S^(c) of ULM-g through ULM-i is CHR^(SS), NR^(URE), or O;    -   R^(HET) of ULM-g through ULM-i is H, CN, NO₂, halo (preferably        Cl or F), optionally substituted C₁-C₆ alkyl (preferably        substituted with one or two hydroxyl groups or up to three halo        groups (e.g. CF₃), optionally substituted O(C₁-C₆ alkyl)        (preferably substituted with one or two hydroxyl groups or up to        three halo groups) or an optionally substituted acetylenic group        —C≡C—R_(a) where R_(a) is H or a C₁-C₆ alkyl group (preferably        C₁-C₃ alkyl);    -   R^(SS) of ULM-g through ULM-i is H, CN, NO₂, halo (preferably F        or Cl), optionally substituted C₁-C₆ alkyl (preferably        substituted with one or two hydroxyl groups or up to three halo        groups), optionally substituted O—(C₁-C₆ alkyl) (preferably        substituted with one or two hydroxyl groups or up to three halo        groups) or an optionally substituted —C(O)(C₁-C₆alkyl)        (preferably substituted with one or two hydroxyl groups or up to        three halo groups);    -   R^(URE) of ULM-g through ULM-i is H, a C₁-C₆ alkyl (preferably H        or C₁-C₃ alkyl) or a —C(O)(C₀-C₆ alkyl), each of which groups is        optionally substituted with one or two hydroxyl groups or up to        three halogen, preferably fluorine groups, or an optionally        substituted heterocycle, for example piperidine, morpholine,        pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine,        piperazine, each of which is optionally substituted;    -   Y^(C) of ULM-g through ULM-i is N or C—R^(YC), where R^(YC) is        H, OH, CN, NO₂, halo (preferably Cl or F), optionally        substituted C₁-C₆ alkyl (preferably substituted with one or two        hydroxyl groups or up to three halo groups (e.g. CF₃),        optionally substituted O(C₁-C₆ alkyl) (preferably substituted        with one or two hydroxyl groups or up to three halo groups) or        an optionally substituted acetylenic group —C≡C—R_(a) where        R_(a) is H or a C₁-C₆ alkyl group (preferably C₁-C₃ alkyl);    -   R^(PRO) of ULM-g through ULM-i is H, optionally substituted        C₁-C₆ alkyl or an optionally substituted aryl (phenyl or        napthyl), heteroaryl or heterocyclic group selected from the        group consisting of oxazole, isoxazole, thiazole, isothiazole,        imidazole, diazole, oximidazole, pyrrole, pyrollidine, furan,        dihydrofuran, tetrahydrofuran, thiene, dihydrothiene,        tetrahydrothiene, pyridine, piperidine, piperazine, morpholine,        quinoline, (each preferably substituted with a C₁-C₃ alkyl        group, preferably methyl or a halo group, preferably F or Cl),        benzofuran, indole, indolizine, azaindolizine;    -   R^(PRO1) and R^(PRO2) of ULM-g through ULM-i are each        independently H, an optionally substituted C₁-C₃ alkyl group or        together form a keto group;    -   each n of ULM-g through ULM-i is independently 0, 1, 2, 3, 4, 5,        or 6 (preferably 0 or 1);    -   each m′ of ULM-g through ULM-i is 0 or 1; and    -   each n′ of ULM-g through ULM-i is 0 or 1;    -   wherein each of said compounds, preferably on the alkyl, Aryl or        Het groups, is optionally connected/coupled to a PTM group        (including a ULM′ group) via a linker.

In alternative embodiments, R^(3′) of ULM-g through ULM-i is—(CH₂)_(n)-Aryl, —(CH₂CH₂O)_(n)-Aryl, —(CH₂)_(n)-HET or—(CH₂CH₂O)_(n)-HET,

wherein:

-   -   said Aryl of ULM-g through ULM-i is phenyl which is optionally        substituted with one or two substitutents, wherein said        substituent(s) is preferably selected from —(CH₂)_(n)OH, C₁-C₆        alkyl which itself is further optionally substituted with CN,        halo (up to three halo groups), OH, —(CH₂)_(n)O(C₁-C₆)alkyl,        amine, mono- or di-(C₁-C₆ alkyl) amine wherein the alkyl group        on the amine is optionally substituted with 1 or 2 hydroxyl        groups or up to three halo (preferably F, C₁) groups, or    -   said Aryl group of ULM-g through ULM-i is substituted with        —(CH₂)_(n)OH, —(CH₂)_(n)—O—(C₁-C₆)alkyl,        —(CH₂)_(n)—O—(CH₂)_(n)—(C₁-C₆)alkyl, —(CH₂)_(n)—C(O)(C₀-C₆)        alkyl, —(CH₂)_(n)—C(O)O(C₀-C₆)alkyl,        —(CH₂)_(n)—OC(O)(C₀-C₆)alkyl, amine, mono- or di-(C₁-C₆ alkyl)        amine wherein the alkyl group on the amine is optionally        substituted with 1 or 2 hydroxyl groups or up to three halo        (preferably F, C₁) groups, CN, NO₂, an optionally substituted        —(CH₂)_(n)—(V)_(m′)—CH₂)_(n)—(V)_(m)—(C₁-C₆)alkyl group, a        —(V)_(m′)—(CH₂CH₂O)_(n)—R^(PEG) group where V is O, S or        NR_(1′), R_(1′) is H or a C₁-C₃ alkyl group (preferably H) and        R^(PEG) is H or a C₁-C₆ alkyl group which is optionally        substituted (including being optionally substituted with a        carboxyl group), or    -   said Aryl group of ULM-g through ULM-i is optionally substituted        with a heterocycle, including a heteroaryl, selected from the        group consisting of oxazole, isoxazole, thiazole, isothiazole,        imidazole, diazole, oximidazole, pyrrole, pyrollidine, furan,        dihydrofuran, tetrahydrofuran, thiene, dihydrothiene,        tetrahydrothiene, pyridine, piperidine, piperazine, morpholine,        quinoline, benzofuran, indole, indolizine, azaindolizine, (when        substituted each preferably substituted with a C₁-C₃ alkyl        group, preferably methyl or a halo group, preferably F or Cl),        or a group according to the chemical structure:

-   -   S^(c) of ULM-g through ULM-i is CHR^(SS), NR^(URE), or O;    -   R^(HET) of ULM-g through ULM-i is H, CN, NO₂, halo (preferably        Cl or F), optionally substituted C₁-C₆ alkyl (preferably        substituted with one or two hydroxyl groups or up to three halo        groups (e.g. CF₃), optionally substituted O(C₁-C₆ alkyl)        (preferably substituted with one or two hydroxyl groups or up to        three halo groups) or an optionally substituted acetylenic group        —C≡C—R_(a) where R_(a) is H or a C₁-C₆ alkyl group (preferably        C₁-C₃ alkyl);    -   R^(SS) of ULM-g through ULM-i is H, CN, NO₂, halo (preferably F        or Cl), optionally substituted C₁-C₆ alkyl (preferably        substituted with one or two hydroxyl groups or up to three halo        groups), optionally substituted 0-(C₁-C₆ alkyl) (preferably        substituted with one or two hydroxyl groups or up to three halo        groups) or an optionally substituted —C(O)(C₁-C₆alkyl)        (preferably substituted with one or two hydroxyl groups or up to        three halo groups);    -   R^(URE) of ULM-g through ULM-i is H, a C₁-C₆ alkyl (preferably H        or C₁-C₃ alkyl) or a —C(O)(C₀-C₆ alkyl), each of which groups is        optionally substituted with one or two hydroxyl groups or up to        three halogen, preferably fluorine groups, or an optionally        substituted heterocycle, for example piperidine, morpholine,        pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine,        piperazine, each of which is optionally substituted;    -   Y^(C) of ULM-g through ULM-i is N or C—R^(YC), where R^(YC) is        H, OH, CN, NO₂, halo (preferably Cl or F), optionally        substituted C₁-C₆ alkyl (preferably substituted with one or two        hydroxyl groups or up to three halo groups (e.g. CF₃),        optionally substituted O(C₁-C₆ alkyl) (preferably substituted        with one or two hydroxyl groups or up to three halo groups) or        an optionally substituted acetylenic group —C≡C—R_(a) where        R_(a) is H or a C₁-C₆ alkyl group (preferably C₁-C₃ alkyl);    -   R^(PRO) of ULM-g through ULM-i is H, optionally substituted        C₁-C₆ alkyl or an optionally substituted aryl (phenyl or        napthyl), heteroaryl or heterocyclic group selected from the        group consisting of oxazole, isoxazole, thiazole, isothiazole,        imidazole, diazole, oximidazole, pyrrole, pyrollidine, furan,        dihydrofuran, tetrahydrofuran, thiene, dihydrothiene,        tetrahydrothiene, pyridine, piperidine, piperazine, morpholine,        quinoline, (each preferably substituted with a C₁-C₃ alkyl        group, preferably methyl or a halo group, preferably F or Cl),        benzofuran, indole, indolizine, azaindolizine;    -   R^(PRO1) and R^(PRO2) of ULM-g through ULM-i are each        independently H, an optionally substituted C₁-C₃ alkyl group or        together form a keto group;    -   HET of ULM-g through ULM-i is preferably oxazole, isoxazole,        thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole,        pyrollidine, furan, dihydrofuran, tetrahydrofuran, thiene,        dihydrothiene, tetrahydrothiene, pyridine, piperidine,        piperazine, morpholine, quinoline, (each preferably substituted        with a C₁-C₃ alkyl group, preferably methyl or a halo group,        preferably F or Cl), benzofuran, indole, indolizine,        azaindolizine, or a group according to the chemical structure:

-   -   S^(c) of ULM-g through ULM-i is CHR^(SS), NR^(U)R^(E), or O;    -   R^(HET) of ULM-g through ULM-i is H, CN, NO₂, halo (preferably        Cl or F), optionally substituted C₁-C₆ alkyl (preferably        substituted with one or two hydroxyl groups or up to three halo        groups (e.g. CF₃), optionally substituted O(C₁-C₆ alkyl)        (preferably substituted with one or two hydroxyl groups or up to        three halo groups) or an optionally substituted acetylenic group        —C≡C—R_(a) where R_(a) is H or a C₁-C₆ alkyl group (preferably        C₁-C₃ alkyl);    -   R^(SS) of ULM-g through ULM-i is H, CN, NO₂, halo (preferably F        or Cl), optionally substituted C₁-C₆ alkyl (preferably        substituted with one or two hydroxyl groups or up to three halo        groups), optionally substituted O—(C₁-C₆ alkyl) (preferably        substituted with one or two hydroxyl groups or up to three halo        groups) or an optionally substituted —C(O)(C₁-C₆alkyl)        (preferably substituted with one or two hydroxyl groups or up to        three halo groups);    -   R^(URE) of ULM-g through ULM-i is H, a C₁-C₆ alkyl (preferably H        or C₁-C₃ alkyl) or a —C(O)(C₀-C₆ alkyl), each of which groups is        optionally substituted with one or two hydroxyl groups or up to        three halogen, preferably fluorine groups, or an optionally        substituted heterocycle, for example piperidine, morpholine,        pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine,        piperazine, each of which is optionally substituted;    -   Y^(C) of ULM-g through ULM-i is N or C—R^(YC), where R^(YC) is        H, OH, CN, NO₂, halo (preferably Cl or F), optionally        substituted C₁-C₆ alkyl (preferably substituted with one or two        hydroxyl groups or up to three halo groups (e.g. CF₃),        optionally substituted O(C₁-C₆ alkyl) (preferably substituted        with one or two hydroxyl groups or up to three halo groups) or        an optionally substituted acetylenic group —C≡C—R_(a) where        R_(a) is H or a C₁-C₆ alkyl group (preferably C₁-C₃ alkyl);    -   R^(PRO) of ULM-g through ULM-i is H, optionally substituted        C₁-C₆ alkyl or an optionally substituted aryl, heteroaryl or        heterocyclic group;    -   R^(PRO1) and R^(PRO2) of ULM-g through ULM-i are each        independently H, an optionally substituted C₁-C₃ alkyl group or        together form a keto group;    -   each m′ of ULM-g through ULM-i is independently 0 or 1; and    -   each n of ULM-g through ULM-i is independently 0, 1, 2, 3, 4, 5,        or 6 (preferably 0 or 1),    -   wherein each of said compounds, preferably on said Aryl or HET        groups, is optionally connected/coupled to a PTM group        (including a ULM′ group) via a linker group.

In still additional embodiments, preferred compounds include thoseaccording to the chemical structure:

wherein:

-   -   R^(1′) of ULM-i is OH or a group which is metabolized in a        patient or subject to OH;    -   R^(2′) of ULM-i is a —NH—CH₂-Aryl-HET (preferably, a phenyl        linked directly to a methyl substituted thiazole);    -   R^(3′) of ULM-i is a —CHR^(CR3′)—NH—C(O)—R^(3P1) group or a        —CHR^(CR3′)—R^(3P2) group;    -   R^(CR3′) of ULM-i is a C₁-C₄ alkyl group, preferably methyl,        isopropyl or tert-butyl;    -   R^(3P1) of ULM-i is C₁-C₃ alkyl (preferably methyl), an        optionally substituted oxetane group (preferably methyl        substituted, a —(CH₂)_(n)OCH₃ group where n is 1 or 2        (preferably 2), or a

group (the ethyl ether group is preferably meta-substituted on thephenyl moiety), a morpholino group (linked to the carbonyl at the 2- or3-position;

-   -   R^(3P2) of ULM-i is a

group;

-   -   Aryl of ULM-i is phenyl;    -   HET of ULM-i is an optionally substituted thiazole or        isothiazole; and    -   R^(HET) of ULM-i is H or a halo group (preferably H);    -   or a pharmaceutically acceptable salt, stereoisomer, solvate or        polymorph thereof, wherein each of said compounds is optionally        connected/coupled to a PTM group (including a ULM′ group) via a        linker group.

In certain aspects, bifunctional compounds comprising a ubiquitin E3ligase binding moiety (ULM), wherein ULM is a group according to thechemical structure:

-   -   wherein:    -   each R₅ and R₆ of ULM-j is independently OH, SH, or optionally        substituted alkyl or R₅, R₆, and the carbon atom to which they        are attached form a carbonyl;    -   R₇ of ULM-j is H or optionally substituted alkyl;    -   E of ULM-j is a bond, C═O, or C═S;    -   G of ULM-j is a bond, optionally substituted alkyl, —COOH or        C=J;    -   J of ULM-j is O or N—R⁸;    -   R₈ of ULM-j is H, CN, optionally substituted alkyl or optionally        substituted alkoxy;    -   M of ULM-j is optionally substituted aryl, optionally        substituted heteroaryl, optionally substituted heterocyclic or

-   -   each R₉ and R₁₀ of ULM-j is independently H; optionally        substituted alkyl, optionally substituted cycloalkyl, optionally        substituted hydroxyalkyl, optionally substituted thioalkyl, a        disulphide linked ULM, optionally substituted heteroaryl, or        haloalkyl; or R₉, R₁₀, and the carbon atom to which they are        attached form an optionally substituted cycloalkyl;    -   R₁₁ of ULM-j is optionally substituted heterocyclic, optionally        substituted alkoxy, optionally substituted heteroaryl,        optionally substituted aryl, or

-   -   R₁₂ of ULM-j is H or optionally substituted alkyl;    -   R₁₃ of ULM-j is H, optionally substituted alkyl, optionally        substituted alkylcarbonyl, optionally substituted        (cycloalkyl)alkylcarbonyl, optionally substituted        aralkylcarbonyl, optionally substituted arylcarbonyl, optionally        substituted (heterocyclyl)carbonyl, or optionally substituted        aralkyl; optionally substituted (oxoalkyl)carbamate,    -   each R₁₄ of ULM-j is independently H, haloalkyl, optionally        substituted cycloalkyl, optionally substituted alkyl or        optionally substituted heterocycloalkyl;    -   R₁₅ of ULM-j is H, optionally substituted heteroaryl, haloalkyl,        optionally substituted aryl, optionally substituted alkoxy, or        optionally substituted heterocyclyl;    -   each R₁₆ of ULM-j is independently halo, optionally substituted        alkyl, optionally substituted haloalkyl, CN, or optionally        substituted haloalkoxy;    -   each R₂₅ of ULM-j is independently H or optionally substituted        alkyl; or both R₂₅ groups can be taken together to form an oxo        or optionally substituted cycloalkyl group;    -   R₂₃ of ULM-j is H or OH;    -   Z₁, Z₂, Z₃, and Z₄ of ULM-j are independently C or N; and    -   of ULM-j is 0, 1, 2, 3, or 4, or a pharmaceutically acceptable        salt, stereoisomer, solvate or polymorph thereof.

In certain embodiments, wherein G of ULM-j is C=J, J is O, R₇ is H, eachR₁₄ is H, and o is O.

In certain embodiments, wherein G of ULM-j is C=J, J is O, R₇ is H, eachR₁₄ is H, R₁₅ is optionally substituted heteroaryl, and o is O. In otherinstances, E is C═O and M is

In certain embodiments, wherein E of ULM-j is C═O, R₁₁ is optionallysubstituted heterocyclic or

and M is

In certain embodiments, wherein E of ULM-j is C═O, M is

and R₁₁ is

each R₁₈ is independently halo, optionally substituted alkoxy, cyano,optionally substituted alkyl, haloalkyl, or haloalkoxy; and p is 0, 1,2, 3, or 4.

In certain embodiments, ULM and where present, ULM′, are eachindependently a group according to the chemical structure:

wherein:

-   -   G of ULM-k is C=J, J is O;    -   R₇ of ULM-k is H;    -   each R₁₄ of ULM-k is H;    -   o of ULM-k is 0;    -   R₁₅ of ULM-k is

and

-   -   R₁₇ of ULM-k is H, halo, optionally substituted cycloalkyl,        optionally substituted alkyl, optionally substituted alkenyl,        and haloalkyl.

In other instances, R₁₇ of ULM-k is alkyl (e.g., methyl) or cycloalkyl(e.g., cyclopropyl).

In other embodiments, ULM and where present, ULM′, are eachindependently a group according to the chemical structure:

wherein:

-   -   G of ULM-k is C=J, J is O;    -   R₇ of ULM-k is H;    -   each R₁₄ of ULM-k is H;    -   o of ULM-k is O; and    -   R₁₅ of ULM-k is selected from the group consisting of:

wherein R₃₀ of ULM-k is H or an optionally substituted alkyl.

In other embodiments, ULM and where present, ULM′, are eachindependently a group according to the chemical structure:

wherein:

-   -   E of ULM-k is C═O;    -   M of ULM-k is

and

-   -   R₁₁ of ULM-k is selected from the group consisting of:

In still other embodiments, a compound of the chemical structure

wherein E of ULM-k is C═O;

-   -   R₁₁ of ULM-k is

andM of ULM-k is

q of ULM-k is 1 or 2;

-   -   R₂₀ of ULM-k is H, optionally substituted alkyl, optionally        substituted cycloalkyl, optionally substituted aryl, or

R₂₁ of ULM-k is H or optionally substituted alkyl; and

-   -   R₂₂ of ULM-k is H, optionally substituted alkyl, optionally        substituted alkoxy, or haloalkyl.

In any embodiment described herein, R₁₁ of ULM-j or ULM-k is selectedfrom the group consisting of:

In certain embodiments, R₁₁ of ULM-j or ULM-k is selected from the groupconsisting of:

In certain embodiments, ULM (or when present ULM′) is a group accordingto the chemical structure:

wherein:

-   -   X of ULM-1 is O or S;    -   Y of ULM-1 is H, methyl or ethyl;    -   R₁₇ of ULM-1 is H, methyl, ethyl, hydoxymethyl or cyclopropyl;    -   M of ULM-1 is optionally substituted aryl, optionally        substituted heteroaryl, or

-   -   R⁹ of ULM-1 is H;    -   R₁₀ of ULM-1 is H, optionally substituted alkyl, optionally        substituted haloalkyl, optionally substituted heteroaryl,        optionally substituted aryl, optionally substituted        hydroxyalkyl, optionally substituted thioalkyl or cycloalkyl;    -   R11 of ULM-1 is optionally substituted heteroaromatic,        optionally substituted heterocyclic, optionally substituted aryl        or

-   -   R₁₂ of ULM-1 is H or optionally substituted alkyl; and    -   R₁₃ of ULM-1 is H, optionally substituted alkyl, optionally        substituted alkylcarbonyl, optionally substituted        (cycloalkyl)alkylcarbonyl, optionally substituted        aralkylcarbonyl, optionally substituted arylcarbonyl, optionally        substituted (heterocyclyl)carbonyl, or optionally substituted        aralkyl; optionally substituted (oxoalkyl)carbamate.

In some embodiments, ULM and where present, ULM′, are each independentlya group according to the chemical structure:

wherein:

-   -   Y of ULM-m is H, methyol or ethyl    -   R₉ of ULM-m is H;    -   R₁₀ is isopropyl, tert-butyl, sec-butyl, cyclopentyl, or        cyclohexyl;    -   R₁₁ of ULM-m is optionally substituted amide, optionally        substituted isoindolinone, optionally substituted isooxazole,        optionally substituted heterocycles.

In other preferred embodiments of the disclosure, ULM and where present,ULM′, are each independently a group according to the chemicalstructure:

wherein:

-   -   R₁₇ of ULM-n is methyl, ethyl, or cyclopropyl; and    -   R₉, R₁₀, and R₁₁ of ULM-n are as defined above. In other        instances, R₉ is H; and    -   R₁₀ of ULM-n is H, alkyl, or cycloalkyl (preferably, isopropyl,        tert-butyl, sec-butyl, cyclopentyl, or cyclohexyl).

In any of the aspects or embodiments described herein, the ULM (or whenpresent, ULM′) as described herein may be a pharmaceutically acceptablesalt, enantiomer, diastereomer, solvate or polymorph thereof. Inaddition, in any of the aspects or embodiments described herein, the ULM(or when present, ULM′) as described herein may be coupled to a PTMdirectly via a bond or by a chemical linker.

In certain aspects of the disclosure, the ULM moiety is selected fromthe group consisting of:

wherein the VLM may be connected to a PTM via a linker, as describedherein, at any appropriate location, including, e.g., an aryl,heteroary, phenyl, or phenyl of an indole group, optionally via anyappropriate functional group, such as an amine, ester, ether, alkyl, oralkoxy.Exemplary Linkers

In certain embodiments, the compounds as described herein include one ormore PTMs chemically linked or coupled to one or more ULMs (e.g., atleast one of CLM, VLM, MLM, ILM, or a combination thereof) via achemical linker (L). In certain embodiments, the linker group L is agroup comprising one or more covalently connected structural units(e.g., -A^(L) ₁ . . . A^(L) _(q)- or -(A^(L))_(q)-), wherein A^(L) ₁ isa group coupled to PTM, and (A^(L))_(q) is a group coupled to ULM.

In certain embodiments, the linker group L is selected from-(A^(L))_(q)-:

-   -   (A^(L))q is a group which is connected to at least one of a ULM        (such as CLM or a VLM), PTM moiety, or a combination thereof;    -   q of the linker is an integer greater than or equal to 1;    -   each A^(L) is independently selected from the group consisting        of, a bond, CR^(L1)R^(L2), O, S, SO, SO₂, NR^(L3), SO₂NR^(L3),        SONR^(L3), CONR^(L3), NR^(L3)CONR^(L4), NR^(L3)SO₂NR^(L4), CO,        CR^(L1)═CR^(L2), C≡C, SiR^(L1)R^(L2), P(O)R^(L1), P(O)OR^(L1),        NR^(L3)C(═NCN)NR^(L4), NR^(L3)C(═NCN), NR^(L3)C(═CNO₂)NR^(L4),        C₃₋₁₁cycloalkyl optionally substituted with 0-6 R^(L1) and/or        R^(L2) groups, C₅₋₁₃ spirocycloalkyl optionally substituted with        0-9 R^(L1) and/or R^(L2) groups, C₃₋₁₁ heterocyclyl optionally        substituted with 0-6 R^(L1) and/or R^(L2) groups, C₅₋₁₃        spiroheterocycloalkyl optionally substituted with 0-8 R^(L1)        and/or R^(L2) groups, aryl optionally substituted with 0-6        R^(L1) and/or R^(L2) groups, heteroaryl optionally substituted        with 0-6 R^(L1) and/or R^(L2) groups, where R^(L1) or R^(L2),        each independently are optionally linked to other groups to form        cycloalkyl and/or heterocyclyl moiety, optionally substituted        with 0-4 R^(L5) groups; and    -   R^(L1), R^(L2), R^(L3), R^(L4) and R^(L5) are, each        independently, H, halo, C₁₋₈alkyl, OC¹⁻⁸alkyl, SC₁₋₈alkyl,        NHC₁₋₈alkyl, N(C₁₋₈alkyl)₂, C₃₋₁₁cycloalkyl, aryl, heteroaryl,        C₃₋₁₁heterocyclyl, OC₁₋₈cycloalkyl, SC₁₋₈cycloalkyl,        NHC₁₋₈cycloalkyl, N(C₁₋₈cycloalkyl)₂,        N(C₁₋₈cycloalkyl)(C₁₋₈alkyl), OH, NH₂, SH, SO₂C₁₋₈alkyl,        P(O)(OC₁₋₈alkyl)(C₁₋₈alkyl), P(O)(OC₁₋₈alkyl)₂, CC—C₁₋₈alkyl,        CCH, CH═CH(C₁₋₈alkyl), C(C₁₋₈alkyl)═CH(C₁₋₈alkyl),        C(C₁₋₈alkyl)═C(C₁₋₈alkyl)₂, Si(OH)₃, Si(C₁₋₈alkyl)₃,        Si(OH)(C₁₋₈alkyl)₂, COC₁₋₈alkyl, CO₂H, halogen, CN, CF₃, CHF₂,        CH₂F, NO₂, SF₅, SO₂NHC₁₋₈alkyl, SO₂N(C₁₋₈alkyl)₂, SONHC₁₋₈alkyl,        SON(C₁₋₈alkyl)₂, CONHC₁₋₈alkyl, CON(C₁₋₈alkyl)₂,        N(C₁₋₈alkyl)CONH(C₁₋₈alkyl), N(C₁₋₈alkyl)CON(C₁₋₈alkyl)₂,        NHCONH(C₁₋₈alkyl), NHCON(C₁₋₈alkyl)₂, NHCONH₂,        N(C₁₋₈alkyl)SO₂NH(C₁₋₈alkyl), N(C₁₋₈alkyl) SO₂N(C₁₋₈alkyl)₂, NH        SO₂NH(C₁₋₈alkyl), NH SO₂N(C₁₋₈alkyl)₂, NH SO₂NH₂.

In certain embodiments, q of the linker is an integer greater than orequal to 0. In certain embodiments, q is an integer greater than orequal to 1.

In certain embodiments, e.g., where q of the linker is greater than 2,A^(L) _(q) is a group which is connected to ULM, and A^(L) ₁ and A^(L)_(q) are connected via structural units of the linker (L).

In certain embodiments, e.g., where q of the linker is 2, A^(L) _(q) isa group which is connected to A^(L) ₁ and to a ULM.

In certain embodiments, e.g., where q of the linker is 1, the structureof the linker group L is -A^(L) ₁-, and A^(L) ₁ is a group which isconnected to a ULM moiety and a PTM moiety.

In certain embodiments, the linker (L) comprises a group represented bya general structure selected from the group consisting of:

-   -   —NR(CH₂)_(n)-(lower alkyl)-, —NR(CH₂)_(n)-(lower alkoxyl)-,        —NR(CH₂)_(n)-(lower alkoxyl)-OCH₂—, —NR(CH₂)_(n)-(lower        alkoxyl)-(lower alkyl)-OCH₂—, —NR(CH₂)_(n)-(cycloalkyl)-(lower        alkyl)-OCH₂—, —NR(CH₂)_(n)-(hetero cycloalkyl)-,        —NR(CH₂CH₂O)_(n)-(lower alkyl)-O—CH₂—, —NR(CH₂CH₂O)_(n)-(hetero        cycloalkyl)-O—CH₂—, —NR(CH₂CH₂O)_(n)-Aryl-O—CH₂—,        —NR(CH₂CH₂O)_(n)-(hetero aryl)-O—CH₂—, —NR(CH₂CH₂O)_(n)-(cyclo        alkyl)-O-(hetero aryl)-O—CH₂—, —NR(CH₂CH₂O)_(n)-(cyclo        alkyl)-O-Aryl-O—CH₂—, —NR(CH₂CH₂O)_(n)-(lower        alkyl)-NH-Aryl-O—CH₂—, —NR(CH₂CH₂O)_(n)-(lower        alkyl)-O-Aryl-CH₂, —NR(CH₂CH₂O)_(n)-cycloalkyl-O-Aryl-,        —NR(CH₂CH₂O)_(n)-cycloalkyl-O-(hetero aryl)l-,        —NR(CH₂CH₂)_(n)-(cycloalkyl)-O-(heterocycle)-CH₂,        —NR(CH₂CH₂)_(n)-(heterocycle)-(heterocycle)-CH₂,        —N(R¹R²)-(heterocycle)-CH₂; where    -   n of the linker can be 0 to 10;    -   R of the linker can be H, lower alkyl;    -   R1 and R2 of the linker can form a ring with the connecting N.

In any aspect or embodiment described herein, the linker (L) comprises agroup represented by a structure selected from the group consisting of:

wherein n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

In certain embodiments, the linker (L) comprises a group represented bya general structure selected from the group consisting of:

-   -   —N(R)—(CH₂)_(m)—O(CH₂)_(n)—O(CH₂)_(o)—O(CH₂)_(p)—O(CH₂)_(q)—O(CH₂)_(r)—OCH₂—,        —O—(CH₂)_(m)—O(CH₂)_(n)—O(CH₂)_(o)—O(CH₂)_(p)—O(CH₂)_(q)—O(CH₂)_(r)—OCH₂—,        —O—(CH₂)_(m)—O(CH₂)_(n)—O(CH₂)_(o)—O(CH₂)_(p)—O(CH₂)_(q)—O(CH₂)_(r)—O—;        —N(R)—(CH₂)_(m)—O(CH₂)_(n)—O(CH₂)_(o)—O(CH₂)_(p)—O(CH₂)_(q)—O(CH₂)_(r)—O—;        —(CH₂)_(m)—O(CH₂)_(n)—O(CH₂)_(o)—O(CH₂)_(p)—O(CH₂)_(q)—O(CH₂)_(r)—O—;        —(CH₂)_(m)—O(CH₂)_(n)—O(CH₂)_(o)—O(CH₂)_(p)—O(CH₂)_(q)—O(CH₂)_(r)—OCH₂—;

wherein

-   -   m, n, o, p, q, and r of the linker are independently 0, 1, 2, 3,        4, 5, 6;    -   when the number is zero, there is no N—O or O—O bond    -   R of the linker is H, methyl and ethyl;    -   X of the linker is H and F

-   -   where m of the linker can be 2, 3, 4, 5

wherein each n and m of the linker can independently be 0, 1, 2, 3, 4,5, 6.

In any aspect or embodiment described herein, the linker (L) is selectedfrom the group consisting of:

wherein each m and n are independently 0, 1, 2, 3, 4, 5, or 6.

In any aspect or embodiment described herein, the linker (L) is selectedfrom the group consisting of:

wherein each m, n, o, p, q, and r is independently 0, 1, 2, 3, 4, 5, 6,or 7.

In any aspect or embodiment described herein, L is selected from thegroup consisting of:

In additional embodiments, the linker (L) comprises a structure selectedfrom, but not limited to the structure shown below, where a dashed lineindicates the attachment point to the PTM or ULM moieties.

wherein:

-   -   W^(L1) and W^(L2) are each independently a 4-8 membered ring        with 0-4 heteroatoms, optionally substituted with R^(Q), each        R^(Q) is independently a H, halo, OH, CN, CF₃, C₁-C₆ alkyl        (linear, branched, optionally substituted), C₁-C₆ alkoxy        (linear, branched, optionally substituted), or 2 R^(Q) groups        taken together with the atom they are attached to, form a 4-8        membered ring system containing 0-4 heteroatoms;    -   Y^(L1) is each independently a bond, C₁-C₆ alkyl (linear,        branched, optionally substituted) and optionally one or more C        atoms are replaced with 0; or C₁-C₆ alkoxy (linear, branched,        optionally substituted);    -   n is 0-10; and    -   a dashed line indicates the attachment point to the PTM or ULM        moieties.

In additional embodiments, the linker (L) comprises a structure selectedfrom, but not limited to the structure shown below, where a dashed lineindicates the attachment point to the PTM or ULM moieties.

wherein:

-   -   W^(L1) and W^(L2) are each independently aryl, heteroaryl,        cyclic, heterocyclic, C₁₋₆ alkyl, bicyclic, biaryl,        biheteroaryl, or biheterocyclic, each optionally substituted        with R^(Q), each R^(Q) is independently a H, halo, OH, CN, CF₃,        hydroxyl, nitro, C≡CH, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁-C₆ alkyl        (linear, branched, optionally substituted), C₁-C₆ alkoxy        (linear, branched, optionally substituted), OC₁₋₃alkyl        (optionally substituted by 1 or more —F), OH, NH₂,        NR^(Y1)R^(Y2), CN, or 2 R^(Q) groups taken together with the        atom they are attached to, form a 4-8 membered ring system        containing 0-4 heteroatoms;    -   Y^(L1) is each independently a bond, NR^(YL1), O, S, NR^(YL2),        CR^(YL1)R^(YL2), C═O, C═S, SO, SO₂, C₁-C₆alkyl (linear,        branched, optionally substituted) and optionally one or more C        atoms are replaced with O; C₁-C₆ alkoxy (linear, branched,        optionally substituted);    -   Q^(L) is a 3-6 membered alicyclic or aromatic ring with 0-4        heteroatoms, optionally bridged, optionally substituted with 0-6        R^(Q), each R^(Q) is independently H, C₁₋₆ alkyl (linear,        branched, optionally substituted by 1 or more halo, C₁₋₆        alkoxyl), or 2 R^(Q) groups taken together with the atom they        are attached to, form a 3-8 membered ring system containing 0-2        heteroatoms);    -   R^(YL1), R^(YL2) are each independently H, OH, C₁₋₆ alkyl        (linear, branched, optionally substituted by 1 or more halo,        C₁₋₆ alkoxyl), or R¹, R² together with the atom they are        attached to, form a 3-8 membered ring system containing 0-2        heteroatoms);    -   n is 0-10; and    -   a dashed line indicates the attachment point to the PTM or ULM        moieties.

In additional embodiments, the linker group is optionally substituted(poly)ethyleneglycol having between 1 and about 100 ethylene glycolunits, between about 1 and about 50 ethylene glycol units, between 1 andabout 25 ethylene glycol units, between about 1 and 10 ethylene glycolunits, between 1 and about 8 ethylene glycol units and 1 and 6 ethyleneglycol units, between 2 and 4 ethylene glycol units, or optionallysubstituted alkyl groups interdispersed with optionally substituted, O,N, S, P or Si atoms. In certain embodiments, the linker is substitutedwith an aryl, phenyl, benzyl, alkyl, alkylene, or heterocycle group. Incertain embodiments, the linker may be asymmetric or symmetrical.

In any of the embodiments of the compounds described herein, the linkergroup may be any suitable moiety as described herein. In one embodiment,the linker is a substituted or unsubstituted polyethylene glycol groupranging in size from about 1 to about 12 ethylene glycol units, between1 and about 10 ethylene glycol units, about 2 about 6 ethylene glycolunits, between about 2 and 5 ethylene glycol units, between about 2 and4 ethylene glycol units.

In another embodiment, the present disclosure is directed to a compoundwhich comprises a PTM group as described above, which binds to a targetprotein (e.g., EZH2) or polypeptide, which is ubiquitinated by anubiquitin ligase and is chemically linked directly to the ULM group orthrough a linker moiety L, or PTM is alternatively a ULM′ group which isalso a ubiquitin ligase binding moiety, which may be the same ordifferent than the ULM group as described above and is linked directlyto the ULM group directly or through the linker moiety; and L is alinker moiety as described above which may be present or absent andwhich chemically (covalently) links ULM to PTM, or a pharmaceuticallyacceptable salt, enantiomer, stereoisomer, solvate or polymorph thereof.

In certain embodiments, the linker group L is a group comprising one ormore covalently connected structural units independently selected fromthe group consisting of:

The X is selected from the group consisting of O, N, S, S(O) and SO₂; nis integer from 1-5, 5; R^(L1) is hydrogen or alkyl,

is a mono- or bicyclic aryl or heteroaryl optionally substituted with1-3 substituents selected from alkyl, halogen, haloalkyl, hydroxy,alkoxy or cyano;

is a mono- or bicyclic cycloalkyl or a heterocycloalkyl optionallysubstituted with 1-3 substituents selected from alkyl, halogen,haloalkyl, hydroxy, alkoxy or cyano; and the phenyl ring fragment can beoptionally substituted with 1, 2 or 3 substituents selected from thegroup consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy andcyano. In an embodiment, the linker group L comprises up to 10covalently connected structural units, as described above.

Although the ULM group and PTM group may be covalently linked to thelinker group through any group which is appropriate and stable to thechemistry of the linker, in preferred aspects of the present disclosure,the linker is independently covalently bonded to the ULM group and thePTM group preferably through an amide, ester, thioester, keto group,carbamate (urethane), carbon or ether, each of which groups may beinserted anywhere on the ULM group and PTM group to provide maximumbinding of the ULM group on the ubiquitin ligase and the PTM group onthe target protein to be degraded. (It is noted that in certain aspectswhere the PTM group is a ULM group, the target protein for degradationmay be the ubiquitin ligase itself). In certain preferred aspects, thelinker may be linked to an optionally substituted alkyl, alkylene,alkene or alkyne group, an aryl group or a heterocyclic group on the ULMand/or PTM groups.

Exemplary PTMs

In preferred aspects of the disclosure, the PTM group is a group, whichbinds to target proteins. Targets of the PTM group are numerous in kindand are selected from proteins that are expressed in a cell such that atleast a portion of the sequences is found in the cell and may bind to aPTM group. The term “protein” includes oligopeptides and polypeptidesequences of sufficient length that they can bind to a PTM groupaccording to the present disclosure. Any protein in a eukaryotic systemor a microbial system, including a virus, bacteria or fungus, asotherwise described herein, are targets for ubiquitination mediated bythe compounds according to the present disclosure. Preferably, thetarget protein is a eukaryotic protein, such as EZH2.

PTM groups according to the present disclosure include, for example, anymoiety which binds to a protein specifically (binds to a target protein)and includes the following non-limiting examples of small moleculetarget protein moieties: histone-lysine N-methyltransferase, Hsp90inhibitors, kinase inhibitors, EZH2 inhibitors, HDM2 & MDM2 inhibitors,compounds targeting Human BET Bromodomain-containing proteins, HDACinhibitors, human lysine methyltransferase inhibitors, angiogenesisinhibitors, nuclear hormone receptor compounds, immunosuppressivecompounds, and compounds targeting the aryl hydrocarbon receptor (AHR),among numerous others. The compositions described below exemplify someof the members of small molecule target protein binding moieties. Suchsmall molecule target protein binding moieties also includepharmaceutically acceptable salts, enantiomers, solvates and polymorphsof these compositions, as well as other small molecules that may targeta protein of interest. These binding moieties are linked to theubiquitin ligase binding moiety preferably through a linker in order topresent a target protein (to which the protein target moiety is bound)in proximity to the ubiquitin ligase for ubiquitination and degradation.

Any protein, which can bind to a protein target moiety or PTM group andacted on or degraded by a ubiquitin ligase is a target protein accordingto the present disclosure. In general, target proteins may include, forexample, structural proteins, receptors, enzymes, cell surface proteins,proteins pertinent to the integrated function of a cell, includingproteins involved in catalytic activity, aromatase activity, motoractivity, helicase activity, metabolic processes (anabolism andcatrabolism), antioxidant activity, proteolysis, biosynthesis, proteinswith kinase activity, oxidoreductase activity, transferase activity,hydrolase activity, lyase activity, isomerase activity, ligase activity,enzyme regulator activity, signal transducer activity, structuralmolecule activity, binding activity (protein, lipid carbohydrate),receptor activity, cell motility, membrane fusion, cell communication,regulation of biological processes, development, cell differentiation,response to stimulus, behavioral proteins, cell adhesion proteins,proteins involved in cell death, proteins involved in transport(including protein transporter activity, nuclear transport, iontransporter activity, channel transporter activity, carrier activity,permease activity, secretion activity, electron transporter activity,pathogenesis, chaperone regulator activity, nucleic acid bindingactivity, transcription regulator activity, extracellular organizationand biogenesis activity, translation regulator activity. Proteins ofinterest can include proteins from eurkaryotes and prokaryotes includinghumans as targets for drug therapy, other animals, includingdomesticated animals, microbials for the determination of targets forantibiotics and other antimicrobials and plants, and even viruses, amongnumerous others.

The present disclosure may be used to treat a number of disease statesand/or conditions, including any disease state and/or condition in whichproteins are dysregulated and where a patient would benefit from thedegradation of proteins.

In an additional aspect, the description provides therapeuticcompositions comprising an effective amount of a compound as describedherein or salt form thereof, and a pharmaceutically acceptable carrier,additive or excipient, and optionally an additional bioactive agent. Thetherapeutic compositions modulate protein degradation in a patient orsubject, for example, an animal such as a human, and can be used fortreating or ameliorating disease states or conditions which aremodulated through the degraded protein. In certain embodiments, thetherapeutic compositions as described herein may be used to effectuatethe degradation of proteins of interest for the treatment oramelioration of a disease, e.g., cancer. In certain additionalembodiments, the disease is breast cancer, prostate cancer, bladdercancer, uterine cancer, renal cancer, melanoma, and/or lymphoma.

In alternative aspects, the present disclosure relates to a method fortreating a disease state or ameliorating the symptoms of a disease orcondition in a subject in need thereof by degrading a protein orpolypeptide through which a disease state or condition is modulatedcomprising administering to said patient or subject an effective amount,e.g., a therapeutically effective amount, of at least one compound asdescribed hereinabove, optionally in combination with a pharmaceuticallyacceptable carrier, additive or excipient, and optionally an additionalbioactive agent, wherein the composition is effective for treating orameliorating the disease or disorder or symptom thereof in the subject.The method according to the present disclosure may be used to treat alarge number of disease states or conditions including cancer, by virtueof the administration of effective amounts of at least one compounddescribed herein. The disease state or condition may be a disease causedby a microbial agent or other exogenous agent such as a virus, bacteria,fungus, protozoa or other microbe or may be a disease state, which iscaused by overexpression of a protein, which leads to a disease stateand/or condition.

In another aspect, the description provides methods for identifying theeffects of the degradation of proteins of interest in a biologicalsystem using compounds according to the present disclosure.

The term “target protein” is used to describe a protein or polypeptide,which is a target for binding to a compound according to the presentdisclosure and degradation by ubiquitin ligase hereunder. Such smallmolecule target protein binding moieties also include pharmaceuticallyacceptable salts, enantiomers, solvates and polymorphs of thesecompositions, as well as other small molecules that may target a proteinof interest. These binding moieties are linked to at least one ULM group(e.g. VLM, CLM, ILM, and/or MLM) through at least one linker group L.

Target proteins, which may be bound to the protein target moiety anddegraded by the ligase to which the ubiquitin ligase binding moiety isbound, include any protein or peptide, including fragments thereof,analogues thereof, and/or homologues thereof. Target proteins includeproteins and peptides having any biological function or activityincluding structural, regulatory, hormonal, enzymatic, genetic,immunological, contractile, storage, transportation, and signaltransduction. In certain embodiments, the target proteins includestructural proteins, receptors, enzymes, cell surface proteins, proteinspertinent to the integrated function of a cell, including proteinsinvolved in catalytic activity, aromatase activity, motor activity,helicase activity, metabolic processes (anabolism and catrabolism),antioxidant activity, proteolysis, biosynthesis, proteins with kinaseactivity, oxidoreductase activity, transferase activity, hydrolaseactivity, lyase activity, isomerase activity, ligase activity, enzymeregulator activity, signal transducer activity, structural moleculeactivity, binding activity (protein, lipid carbohydrate), receptoractivity, cell motility, membrane fusion, cell communication, regulationof biological processes, development, cell differentiation, response tostimulus, behavioral proteins, cell adhesion proteins, proteins involvedin cell death, proteins involved in transport (including proteintransporter activity, nuclear transport, ion transporter activity,channel transporter activity, carrier activity, permease activity,secretion activity, electron transporter activity, pathogenesis,chaperone regulator activity, nucleic acid binding activity,transcription regulator activity, extracellular organization andbiogenesis activity, translation regulator activity. Proteins ofinterest can include proteins from eurkaryotes and prokaryotes,including microbes, viruses, fungi and parasites, including humans,microbes, viruses, fungi and parasites, among numerous others, astargets for drug therapy, other animals, including domesticated animals,microbials for the determination of targets for antibiotics and otherantimicrobials and plants, and even viruses, among numerous others.

More specifically, a number of drug targets for human therapeuticsrepresent protein targets to which protein target moiety may be boundand incorporated into compounds according to the present disclosure.These include proteins which may be used to restore function in numerouspolygenic diseases, including for example EZH2, B7.1 and B7, TINFRlm,TNFR2, NADPH oxidase, BclIBax and other partners in the apotosispathway, C₅a receptor, HMG-CoA reductase, PDE V phosphodiesterase type,PDE IV phosphodiesterase type 4, PDE I, PDEII, PDEIII, squalene cyclaseinhibitor, CXCR1, CXCR2, nitric oxide (NO) synthase, cyclo-oxygenase 1,cyclo-oxygenase 2, 5HT receptors, dopamine receptors, G Proteins, i.e.,Gq, histamine receptors, 5-lipoxygenase, tryptase serine protease,thymidylate synthase, purine nucleoside phosphorylase, GAPDHtrypanosomal, glycogen phosphorylase, Carbonic anhydrase, chemokinereceptors, JAW STAT, RXR and similar, HIV 1 protease, HIV 1 integrase,influenza, neuramimidase, hepatitis B reverse transcriptase, sodiumchannel, multi drug resistance (MDR), protein P-glycoprotein (and MRP),tyrosine kinases, CD23, CD124, tyrosine kinase p56 lck, CD4, CD5, IL-2receptor, IL-1 receptor, TNF-alphaR, ICAM1, Cat+channels, VCAM, VLA-4integrin, selectins, CD40/CD40L, newokinins and receptors, inosinemonophosphate dehydrogenase, p38 MAP Kinase, RaslRaflMEWERK pathway,interleukin-1 converting enzyme, caspase, HCV, NS3 protease, HCV NS3 RNAhelicase, glycinamide ribonucleotide formyl transferase, rhinovirus 3Cprotease, herpes simplex virus-1 (HSV-I), protease, cytomegalovirus(CMV) protease, poly (ADP-ribose) polymerase, cyclin dependent kinases,vascular endothelial growth factor, oxytocin receptor, microsomaltransfer protein inhibitor, bile acid transport inhibitor, 5 alphareductase inhibitors, angiotensin 11, glycine receptor, noradrenalinereuptake receptor, endothelin receptors, neuropeptide Y and receptor,estrogen receptors, androgen receptors, adenosine receptors, adenosinekinase and AMP deaminase, purinergic receptors (P2Y1, P2Y2, P2Y4, P2Y6,P2X1-7), farnesyltransferases, geranylgeranyl transferase, TrkA areceptor for NGF, beta-amyloid, tyrosine kinase Flk-IIKDR, vitronectinreceptor, integrin receptor, Her-21 neu, telomerase inhibition,cytosolic phospholipaseA2 and EGF receptor tyrosine kinase. Additionalprotein targets include, for example, ecdysone 20-monooxygenase, ionchannel of the GABA gated chloride channel, acetylcholinesterase,voltage-sensitive sodium channel protein, calcium release channel, andchloride channels. Still further target proteins include Acetyl-CoAcarboxylase, adenylosuccinate synthetase, protoporphyrinogen oxidase,and enolpyruvylshikimate-phosphate synthase.

These various protein targets may be used in screens that identifycompound moieties which bind to the protein and by incorporation of themoiety into compounds according to the present disclosure, the level ofactivity of the protein may be altered for therapeutic end result.

The term “protein target moiety” or PTM is used to describe a smallmolecule which binds to a target protein or other protein or polypeptideof interest and places/presents that protein or polypeptide in proximityto an ubiquitin ligase such that degradation of the protein orpolypeptide by ubiquitin ligase may occur. Non-limiting examples ofsmall molecule target protein binding moieties include EZH2 inhibitors,Hsp90 inhibitors, kinase inhibitors, MDM2 inhibitors, compoundstargeting Human BET Bromodomain-containing proteins, HDAC inhibitors,human lysine methyltransferase inhibitors, angiogenesis inhibitors,immunosuppressive compounds, and compounds targeting the arylhydrocarbon receptor (AHR), among numerous others. The compositionsdescribed below exemplify some of the members of the small moleculetarget proteins.

Exemplary protein target moieties according to the present disclosureinclude, haloalkane halogenase inhibitors, EZH2 inhibitors, Hsp90inhibitors, kinase inhibitors, MDM2 inhibitors, compounds targetingHuman BET Bromodomain-containing proteins, HDAC inhibitors, human lysinemethyltransferase inhibitors, angiogenesis inhibitors, immunosuppressivecompounds, and compounds targeting the aryl hydrocarbon receptor (AHR).

The compositions described below exemplify some of the members of thesetypes of small molecule target protein binding moieties. Such smallmolecule target protein binding moieties also include pharmaceuticallyacceptable salts, enantiomers, solvates and polymorphs of thesecompositions, as well as other small molecules that may target a proteinof interest. References which are cited herein below are incorporated byreference herein in their entirety.

In any aspect or embodiment described herein, the PTM or EZH2 bindingmoiety (EBM) is represented by Formula PTM-I, PTM-II, PTM-III, PTM-IVa,PTM-IVb, PTM-V, or PTM-VI:

wherein:

-   -   each W_(PTM), X_(PTM), Y_(PTM), and Z_(PTM) is independently        chosen from C or N, wherein no more than two of W_(PTM),        X_(PTM), Y_(PTM), and Z_(PTM) is N;    -   X_(PTM1) is absent, NH, O, heterocycle (e.g., a 4-6 member        heterocyclic, such as a heterocyclic group with 1-3        N-substitutions);    -   X_(PTM2) is absent, CH₂, NH, O, heterocycle (e.g., a 4-6 member        heterocyclic, such as a heterocyclic group with 1-3        N-substitutions), heteroaryl (e.g., a 4-6 member heteroaryl,        such as a heteroaryl group with 1-3 N-substitutions), or        CH₂-heteroaryl (e.g., a 4-6 member heteroaryl, such as a        heteroaryl group with 1-3 N-substitutions);    -   R_(PTM) is absent, H, short chain alkyl (linear, branched,        optionally substituted), methoxy, or ethoxy;    -   R_(PTM1) is an absent, alkyl, halogen, haloalkyl, or alkoxy;    -   R_(PTM2) and R_(PTM3) are independently a halogen, CN, alkoxy        (e.g., methoxy or ethoxy);    -   R_(PTM4) is a alkyl (linear, branched, optionally substituted)        or a 4-6 member cyclicalkyl

is an optionally substituted C₁-C₄ alkyl that is optionally cyclized tothe adjacent carbon of the pyridinyl ring to which it is attached; and

-   -   indicates a covalent linkage to at least one of a linker (L), a        ULM, a ULM′, a VLM, a VLM′, a CLM, a CLM′, an ILM, an ILM′, a        MLM, a MLM′, or a combination thereof.

In certain embodiments, the

is a methyl group.

In any aspect or embodiment described herein, the PTM is selected fromthe group consisting of:

or a combination thereof, wherein

may be N-substituted.Therapeutic Compositions

Pharmaceutical compositions comprising combinations of an effectiveamount of at least one bifunctional compound as described herein, andone or more of the compounds otherwise described herein, all ineffective amounts, in combination with a pharmaceutically effectiveamount of a carrier, additive or excipient, represents a further aspectof the present disclosure.

The present disclosure includes, where applicable, the compositionscomprising the pharmaceutically acceptable salts, in particular, acid orbase addition salts of compounds as described herein. The acids whichare used to prepare the pharmaceutically acceptable acid addition saltsof the aforementioned base compounds useful according to this aspect arethose which form non-toxic acid addition salts, i.e., salts containingpharmacologically acceptable anions, such as the hydrochloride,hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acidphosphate, acetate, lactate, citrate, acid citrate, tartrate,bitartrate, succinate, maleate, fumarate, gluconate, saccharate,benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate,p-toluenesulfonate and pamoate [i.e., 1,1′-methylene-bis-(2-hydroxy-3naphthoate)]salts, among numerous others.

Pharmaceutically acceptable base addition salts may also be used toproduce pharmaceutically acceptable salt forms of the compounds orderivatives according to the present disclosure. The chemical bases thatmay be used as reagents to prepare pharmaceutically acceptable basesalts of the present compounds that are acidic in nature are those thatform non-toxic base salts with such compounds. Such non-toxic base saltsinclude, but are not limited to those derived from suchpharmacologically acceptable cations such as alkali metal cations (e.g.,potassium and sodium) and alkaline earth metal cations (eg, calcium,zinc and magnesium), ammonium or water-soluble amine addition salts suchas N-methylglucamine-(meglumine), and the lower alkanolammonium andother base salts of pharmaceutically acceptable organic amines, amongothers.

The compounds as described herein may, in accordance with thedisclosure, be administered in single or divided doses by the oral,parenteral or topical routes. Administration of the active compound mayrange from continuous (intravenous drip) to several oral administrationsper day (for example, Q.I.D.) and may include oral, topical, parenteral,intramuscular, intravenous, sub-cutaneous, transdermal (which mayinclude a penetration enhancement agent), buccal, sublingual andsuppository administration, among other routes of administration.Enteric coated oral tablets may also be used to enhance bioavailabilityof the compounds from an oral route of administration. The mosteffective dosage form will depend upon the pharmacokinetics of theparticular agent chosen as well as the severity of disease in thepatient. Administration of compounds according to the present disclosureas sprays, mists, or aerosols for intra-nasal, intra-tracheal orpulmonary administration may also be used. The present disclosuretherefore also is directed to pharmaceutical compositions comprising aneffective amount of compound as described herein, optionally incombination with a pharmaceutically acceptable carrier, additive orexcipient. Compounds according to the present disclosure may beadministered in immediate release, intermediate release or sustained orcontrolled release forms. Sustained or controlled release forms arepreferably administered orally, but also in suppository and transdermalor other topical forms. Intramuscular injections in liposomal form mayalso be used to control or sustain the release of compound at aninjection site.

The compositions as described herein may be formulated in a conventionalmanner using one or more pharmaceutically acceptable carriers and mayalso be administered in controlled-release formulations.Pharmaceutically acceptable carriers that may be used in thesepharmaceutical compositions include, but are not limited to, ionexchangers, alumina, aluminum stearate, lecithin, serum proteins, suchas human serum albumin, buffer substances such as phosphates, glycine,sorbic acid, potassium sorbate, partial glyceride mixtures of saturatedvegetable fatty acids, water, salts or electrolytes, such as prolaminesulfate, disodium hydrogen phosphate, potassium hydrogen phosphate,sodium chloride, zinc salts, colloidal silica, magnesium trisilicate,polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol,sodium carboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat.

The compositions as described herein may be administered orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The term “parenteral”as used herein includes subcutaneous, intravenous, intramuscular,intra-articular, intra-synovial, intrasternal, intrathecal,intrahepatic, intralesional and intracranial injection or infusiontechniques. Preferably, the compositions are administered orally,intraperitoneally or intravenously.

Sterile injectable forms of the compositions as described herein may beaqueous or oleaginous suspension. These suspensions may be formulatedaccording to techniques known in the art using suitable dispersing orwetting agents and suspending agents. The sterile injectable preparationmay also be a sterile injectable solution or suspension in a non-toxicparenterally-acceptable diluent or solvent, for example as a solution in1, 3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose, any bland fixed oilmay be employed including synthetic mono- or di-glycerides. Fatty acids,such as oleic acid and its glyceride derivatives are useful in thepreparation of injectables, as are natural pharmaceutically-acceptableoils, such as olive oil or castor oil, especially in theirpolyoxyethylated versions. These oil solutions or suspensions may alsocontain a long-chain alcohol diluent or dispersant, such as Ph. Helv orsimilar alcohol.

The pharmaceutical compositions as described herein may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, aqueous suspensions or solutions. In thecase of tablets for oral use, carriers which are commonly used includelactose and corn starch. Lubricating agents, such as magnesium stearate,are also typically added. For oral administration in a capsule form,useful diluents include lactose and dried corn starch. When aqueoussuspensions are required for oral use, the active ingredient is combinedwith emulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added.

Alternatively, the pharmaceutical compositions as described herein maybe administered in the form of suppositories for rectal administration.These can be prepared by mixing the agent with a suitable non-irritatingexcipient, which is solid at room temperature but liquid at rectaltemperature and therefore will melt in the rectum to release the drug.Such materials include cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions as described herein may also beadministered topically. Suitable topical formulations are readilyprepared for each of these areas or organs. Topical application for thelower intestinal tract can be effected in a rectal suppositoryformulation (see above) or in a suitable enema formulation.Topically-acceptable transdermal patches may also be used.

For topical applications, the pharmaceutical compositions may beformulated in a suitable ointment containing the active componentsuspended or dissolved in one or more carriers. Carriers for topicaladministration of the compounds of this disclosure include, but are notlimited to, mineral oil, liquid petrolatum, white petrolatum, propyleneglycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax andwater. In certain preferred aspects of the disclosure, the compounds maybe coated onto a stent which is to be surgically implanted into apatient in order to inhibit or reduce the likelihood of occlusionoccurring in the stent in the patient.

Alternatively, the pharmaceutical compositions can be formulated in asuitable lotion or cream containing the active components suspended ordissolved in one or more pharmaceutically acceptable carriers. Suitablecarriers include, but are not limited to, mineral oil, sorbitanmonostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol,2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutical compositions may be formulated asmicronized suspensions in isotonic, pH adjusted sterile saline, or,preferably, as solutions in isotonic, pH adjusted sterile saline, eitherwith our without a preservative such as benzylalkonium chloride.Alternatively, for ophthalmic uses, the pharmaceutical compositions maybe formulated in an ointment such as petrolatum.

The pharmaceutical compositions as described herein may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

The amount of compound in a pharmaceutical composition as describedherein that may be combined with the carrier materials to produce asingle dosage form will vary depending upon the host and diseasetreated, the particular mode of administration. Preferably, thecompositions should be formulated to contain between about 0.05milligram to about 750 milligrams or more, more preferably about 1milligram to about 600 milligrams, and even more preferably about 10milligrams to about 500 milligrams of active ingredient, alone or incombination with at least one other compound according to the presentdisclosure.

It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,rate of excretion, drug combination, and the judgment of the treatingphysician and the severity of the particular disease or condition beingtreated.

A patient or subject in need of therapy using compounds according to themethods described herein can be treated by administering to the patient(subject) an effective amount of the compound according to the presentdisclosure including pharmaceutically acceptable salts, solvates orpolymorphs, thereof optionally in a pharmaceutically acceptable carrieror diluent, either alone, or in combination with other knownerythopoiesis stimulating agents as otherwise identified herein.

These compounds can be administered by any appropriate route, forexample, orally, parenterally, intravenously, intradermally,subcutaneously, or topically, including transdermally, in liquid, cream,gel, or solid form, or by aerosol form.

The active compound is included in the pharmaceutically acceptablecarrier or diluent in an amount sufficient to deliver to a patient atherapeutically effective amount for the desired indication, withoutcausing serious toxic effects in the patient treated. A preferred doseof the active compound for all of the herein-mentioned conditions is inthe range from about 10 ng/kg to 300 mg/kg, preferably 0.1 to 100 mg/kgper day, more generally 0.5 to about 25 mg per kilogram body weight ofthe recipient/patient per day. A typical topical dosage will range from0.01-5% wt/wt in a suitable carrier.

The compound is conveniently administered in any suitable unit dosageform, including but not limited to one containing less than 1 mg, 1 mgto 3000 mg, preferably 5 to 500 mg of active ingredient per unit dosageform. An oral dosage of about 25-250 mg is often convenient.

The active ingredient is preferably administered to achieve peak plasmaconcentrations of the active compound of about 0.00001-30 mM, preferablyabout 0.1-30 μM. This may be achieved, for example, by the intravenousinjection of a solution or formulation of the active ingredient,optionally in saline, or an aqueous medium or administered as a bolus ofthe active ingredient. Oral administration is also appropriate togenerate effective plasma concentrations of active agent.

The concentration of active compound in the drug composition will dependon absorption, distribution, inactivation, and excretion rates of thedrug as well as other factors known to those of skill in the art. It isto be noted that dosage values will also vary with the severity of thecondition to be alleviated. It is to be further understood that for anyparticular subject, specific dosage regimens should be adjusted overtime according to the individual need and the professional judgment ofthe person administering or supervising the administration of thecompositions, and that the concentration ranges set forth herein areexemplary only and are not intended to limit the scope or practice ofthe claimed composition. The active ingredient may be administered atonce, or may be divided into a number of smaller doses to beadministered at varying intervals of time.

Oral compositions will generally include an inert diluent or an ediblecarrier. They may be enclosed in gelatin capsules or compressed intotablets. For the purpose of oral therapeutic administration, the activecompound or its prodrug derivative can be incorporated with excipientsand used in the form of tablets, troches, or capsules. Pharmaceuticallycompatible binding agents, and/or adjuvant materials can be included aspart of the composition.

The tablets, pills, capsules, troches and the like can contain any ofthe following ingredients, or compounds of a similar nature: a bindersuch as microcrystalline cellulose, gum tragacanth or gelatin; anexcipient such as starch or lactose, a dispersing agent such as alginicacid, Primogel, or corn starch; a lubricant such as magnesium stearateor Sterotes; a glidant such as colloidal silicon dioxide; a sweeteningagent such as sucrose or saccharin; or a flavoring agent such aspeppermint, methyl salicylate, or orange flavoring. When the dosage unitform is a capsule, it can contain, in addition to material of the abovetype, a liquid carrier such as a fatty oil. In addition, dosage unitforms can contain various other materials which modify the physical formof the dosage unit, for example, coatings of sugar, shellac, or entericagents.

The active compound or pharmaceutically acceptable salt thereof can beadministered as a component of an elixir, suspension, syrup, wafer,chewing gum or the like. A syrup may contain, in addition to the activecompounds, sucrose as a sweetening agent and certain preservatives, dyesand colorings and flavors.

The active compound or pharmaceutically acceptable salts thereof canalso be mixed with other active materials that do not impair the desiredaction, or with materials that supplement the desired action, such aserythropoietin stimulating agents, including EPO and darbapoietin alfa,among others. In certain preferred aspects of the disclosure, one ormore compounds according to the present disclosure are coadministeredwith another bioactive agent, such as an erythropoietin stimulatingagent or a would healing agent, including an antibiotic, as otherwisedescribed herein.

Solutions or suspensions used for parenteral, intradermal, subcutaneous,or topical application can include the following components: a sterilediluent such as water for injection, saline solution, fixed oils,polyethylene glycols, glycerine, propylene glycol or other syntheticsolvents; antibacterial agents such as benzyl alcohol or methylparabens; antioxidants such as ascorbic acid or sodium bisulfite;chelating agents such as ethylenediaminetetraacetic acid; buffers suchas acetates, citrates or phosphates and agents for the adjustment oftonicity such as sodium chloride or dextrose. The parental preparationcan be enclosed in ampoules, disposable syringes or multiple dose vialsmade of glass or plastic.

If administered intravenously, preferred carriers are physiologicalsaline or phosphate buffered saline (PBS).

In one embodiment, the active compounds are prepared with carriers thatwill protect the compound against rapid elimination from the body, suchas a controlled release formulation, including implants andmicroencapsulated delivery systems. Biodegradable, biocompatiblepolymers can be used, such as ethylene vinyl acetate, polyanhydrides,polyglycolic acid, collagen, polyorthoesters, and polylactic acid.Methods for preparation of such formulations will be apparent to thoseskilled in the art.

Liposomal suspensions may also be pharmaceutically acceptable carriers.These may be prepared according to methods known to those skilled in theart, for example, as described in U.S. Pat. No. 4,522,811 (which isincorporated herein by reference in its entirety). For example, liposomeformulations may be prepared by dissolving appropriate lipid(s) (such asstearoyl phosphatidyl ethanolamine, stearoyl phosphatidyl choline,arachadoyl phosphatidyl choline, and cholesterol) in an inorganicsolvent that is then evaporated, leaving behind a thin film of driedlipid on the surface of the container. An aqueous solution of the activecompound are then introduced into the container. The container is thenswirled by hand to free lipid material from the sides of the containerand to disperse lipid aggregates, thereby forming the liposomalsuspension.

Therapeutic Methods

In an additional aspect, the description provides therapeuticcompositions comprising an effective amount of a compound as describedherein or salt form thereof, and a pharmaceutically acceptable carrier.The therapeutic compositions modulate protein degradation in a patientor subject, for example, an animal such as a human, and can be used fortreating or ameliorating disease states or conditions which aremodulated through the degraded protein.

The terms “treat”, “treating”, and “treatment”, etc., as used herein,refer to any action providing a benefit to a patient for which thepresent compounds may be administered, including the treatment of anydisease state or condition which is modulated through the protein towhich the present compounds bind. Disease states or conditions,including cancer, which may be treated using compounds according to thepresent disclosure are set forth hereinabove.

The description provides therapeutic compositions as described hereinfor effectuating the degradation of proteins of interest for thetreatment or amelioration of a disease, e.g., cancer. In certainadditional embodiments, the disease is multiple myeloma. As such, inanother aspect, the description provides a method ofubiquitinating/degrading a target protein in a cell. In certainembodiments, the method comprises administering a bifunctional compoundas described herein comprising, e.g., a ULM and a PTM, preferably linkedthrough a linker moiety, as otherwise described herein, wherein the ULMis coupled to the PTM and wherein the ULM recognizes a ubiquitin pathwayprotein (e.g., an ubiquitin ligase, such as an E3 ubiquitin ligaseincluding cereblon, VHL, IAP, and/or MDM2) and the PTM recognizes thetarget protein such that degradation of the target protein will occurwhen the target protein is placed in proximity to the ubiquitin ligase,thus resulting in degradation/inhibition of the effects of the targetprotein and the control of protein levels. The control of protein levelsafforded by the present disclosure provides treatment of a disease stateor condition, which is modulated through the target protein by loweringthe level of that protein in the cell, e.g., cell of a patient. Incertain embodiments, the method comprises administering an effectiveamount of a compound as described herein, optionally including apharmaceutically acceptable excipient, carrier, adjuvant, anotherbioactive agent or combination thereof.

In additional embodiments, the description provides methods for treatingor ameliorating a disease, disorder or symptom thereof in a subject or apatient, e.g., an animal such as a human, comprising administering to asubject in need thereof a composition comprising an effective amount,e.g., a therapeutically effective amount, of a compound as describedherein or salt form thereof, and a pharmaceutically acceptableexcipient, carrier, adjuvant, another bioactive agent or combinationthereof, wherein the composition is effective for treating orameliorating the disease or disorder or symptom thereof in the subject.

In another aspect, the description provides methods for identifying theeffects of the degradation of proteins of interest in a biologicalsystem using compounds according to the present disclosure.

In another embodiment, the present disclosure is directed to a method oftreating a human patient in need for a disease state or conditionmodulated through a protein where the degradation of that protein willproduce a therapeutic effect in the patient, the method comprisingadministering to a patient in need an effective amount of a compoundaccording to the present disclosure, optionally in combination withanother bioactive agent. The disease state or condition may be a diseasecaused by a microbial agent or other exogenous agent such as a virus,bacteria, fungus, protozoa or other microbe or may be a disease state,which is caused by overexpression of a protein, which leads to a diseasestate and/or condition

The term “disease state or condition” is used to describe any diseasestate or condition wherein protein dysregulation (i.e., the amount ofprotein expressed in a patient is elevated) occurs and where degradationof one or more proteins in a patient may provide beneficial therapy orrelief of symptoms to a patient in need thereof. In certain instances,the disease state or condition may be cured.

Disease states or conditions which may be treated using compoundsaccording to the present disclosure include, for example, asthma,autoimmune diseases such as multiple sclerosis, various cancers,ciliopathies, cleft palate, diabetes, heart disease, hypertension,inflammatory bowel disease, mental retardation, mood disorder, obesity,refractive error, infertility, Angelman syndrome, Canavan disease,Coeliac disease, Charcot-Marie-Tooth disease, Cystic fibrosis, Duchennemuscular dystrophy, Haemochromatosis, Haemophilia, Klinefelter'ssyndrome, Neurofibromatosis, Phenylketonuria, Polycystic kidney disease,(PKD1) or 4 (PKD2) Prader-Willi syndrome, Sickle-cell disease, Tay-Sachsdisease, Turner syndrome.

The term “neoplasia” or “cancer” is used throughout the specification torefer to the pathological process that results in the formation andgrowth of a cancerous or malignant neoplasm, i.e., abnormal tissue thatgrows by cellular proliferation, often more rapidly than normal andcontinues to grow after the stimuli that initiated the new growth cease.Malignant neoplasms show partial or complete lack of structuralorganization and functional coordination with the normal tissue and mostinvade surrounding tissues, metastasize to several sites, and are likelyto recur after attempted removal and to cause the death of the patientunless adequately treated. As used herein, the term neoplasia is used todescribe all cancerous disease states and embraces or encompasses thepathological process associated with malignant hematogenous, ascitic andsolid tumors. Exemplary cancers which may be treated by the presentcompounds either alone or in combination with at least one additionalanti-cancer agent include squamous-cell carcinoma, basal cell carcinoma,adenocarcinoma, hepatocellular carcinomas, and renal cell carcinomas,cancer of the bladder, bowel, breast, cervix, colon, esophagus, head,kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach;leukemias; benign and malignant lymphomas, particularly Burkitt'slymphoma and Non-Hodgkin's lymphoma; benign and malignant melanomas;myeloproliferative diseases; sarcomas, including Ewing's sarcoma,hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheralneuroepithelioma, synovial sarcoma, gliomas, astrocytomas,oligodendrogliomas, ependymomas, gliobastomas, neuroblastomas,ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors,meningiomas, meningeal sarcomas, neurofibromas, and Schwannomas; bowelcancer, breast cancer, prostate cancer, cervical cancer, uterine cancer,lung cancer, ovarian cancer, testicular cancer, thyroid cancer,astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, livercancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease,Wilms' tumor and teratocarcinomas. Additional cancers which may betreated using compounds according to the present disclosure include, forexample, T-lineage Acute lymphoblastic Leukemia (T-ALL), T-lineagelymphoblastic Lymphoma (T-LL), Peripheral T-cell lymphoma, Adult T-cellLeukemia, Pre-B ALL, Pre-B Lymphomas, Large B-cell Lymphoma, BurkittsLymphoma, B-cell ALL, Philadelphia chromosome positive ALL andPhiladelphia chromosome positive CML.

In any aspect or embodiment described herein, the disease state orcondition is selected from breast cancer, prostate cancer, bladdercancer, uterine cancer, renal cancer, melanoma, and/or lymphoma.

The term “bioactive agent” is used to describe an agent, other than acompound according to the present disclosure, which is used incombination with the present compounds as an agent with biologicalactivity to assist in effecting an intended therapy, inhibition and/orprevention/prophylaxis for which the present compounds are used.Preferred bioactive agents for use herein include those agents whichhave pharmacological activity similar to that for which the presentcompounds are used or administered and include for example, anti-canceragents, antiviral agents, especially including anti-HIV agents andanti-HCV agents, antimicrobial agents, antifungal agents, etc.

The term “additional anti-cancer agent” is used to describe ananti-cancer agent, which may be combined with compounds according to thepresent disclosure to treat cancer. These agents include, for example,everolimus, trabectedin, abraxane, TLK 286, AV-299, DN-101, pazopanib,GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107,TKI-258, GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK-0457,MLN8054, PHA-739358, R-763, AT-9263, a FLT-3 inhibitor, a VEGFRinhibitor, an EGFR TK inhibitor, an aurora kinase inhibitor, a PIK-1modulator, a Bcl-2 inhibitor, an HDAC inhbitor, a c-MET inhibitor, aPARP inhibitor, a Cdk inhibitor, an EGFR TK inhibitor, an IGFR-TKinhibitor, an anti-HGF antibody, a PI3 kinase inhibitor, an AKTinhibitor, an mTORC1/2 inhibitor, a JAK/STAT inhibitor, a checkpoint-1or 2 inhibitor, a focal adhesion kinase inhibitor, a Map kinase kinase(mek) inhibitor, a VEGF trap antibody, pemetrexed, erlotinib, dasatanib,nilotinib, decatanib, panitumumab, amrubicin, oregovomab, Lep-etu,nolatrexed, azd2171, batabulin, ofatumumab, zanolimumab, edotecarin,tetrandrine, rubitecan, tesmilifene, oblimersen, ticilimumab,ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490,cilengitide, gimatecan, IL13-PE38QQR, INO 1001, IPdR1 KRX-0402,lucanthone, LY317615, neuradiab, vitespan, Rta 744, Sdx 102, talampanel,atrasentan, Xr 311, romidepsin, ADS-100380, sunitinib, 5-fluorouracil,vorinostat, etoposide, gemcitabine, doxorubicin, liposomal doxorubicin,5′-deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709,seliciclib; PD0325901, AZD-6244, capecitabine, L-Glutamic acid,N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-,disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan,tamoxifen, toremifene citrate, anastrazole, exemestane, letrozole,DES(diethylstilbestrol), estradiol, estrogen, conjugated estrogen,bevacizumab, IMC-1C11, CHIR-258);3-[5-(methylsulfonylpiperadinemethyl)-indolyl-quinolone, vatalanib,AG-013736, AVE-0005, goserelin acetate, leuprolide acetate, triptorelinpamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate,megestrol acetate, raloxifene, bicalutamide, flutamide, nilutamide,megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatanib,canertinib, ABX-EGF antibody, erbitux, EKB-569, PKI-166, GW-572016,Ionafarnib, BMS-214662, tipifarnib; amifostine, NVP-LAQ824, suberoylanalide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248,sorafenib, KRN951, aminoglutethimide, arnsacrine, anagrelide,L-asparaginase, Bacillus Calmette-Guerin (BCG) vaccine, adriamycin,bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil,cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine,dactinomycin, daunorubicin, diethylstilbestrol, epirubicin, fludarabine,fludrocortisone, fluoxymesterone, flutamide, gleevec, gemcitabine,hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole,lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna,methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide,oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer,procarbazine, raltitrexed, rituximab, streptozocin, teniposide,testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine,13-cis-retinoic acid, phenylalanine mustard, uracil mustard,estramustine, altretamine, floxuridine, 5-deooxyuridine, cytosinearabinoside, 6-mecaptopurine, deoxycoformycin, calcitriol, valrubicin,mithramycin, vinblastine, vinorelbine, topotecan, razoxin, marimastat,COL-3, neovastat, BMS-275291, squalamine, endostatin, SU5416, SU6668,EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene,idoxyfene, spironolactone, finasteride, cimitidine, trastuzumab,denileukin diftitox, gefitinib, bortezimib, paclitaxel, cremophor-freepaclitaxel, docetaxel, epithilone B, BMS-247550, BMS-310705,droloxifene, 4-hydroxytamoxifen, pipendoxifene, ERA-923, arzoxifene,fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR-3339,ZK186619, topotecan, PTK787/ZK 222584, VX-745, PD 184352, rapamycin,40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001,ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646,wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin,erythropoietin, granulocyte colony-stimulating factor, zolendronate,prednisone, cetuximab, granulocyte macrophage colony-stimulating factor,histrelin, pegylated interferon alfa-2a, interferon alfa-2a, pegylatedinterferon alfa-2b, interferon alfa-2b, azacitidine, PEG-L-asparaginase,lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane,alemtuzumab, all-transretinoic acid, ketoconazole, interleukin-2,megestrol, immune globulin, nitrogen mustard, methylprednisolone,ibritgumomab tiuxetan, androgens, decitabine, hexamethylmelamine,bexarotene, tositumomab, arsenic trioxide, cortisone, editronate,mitotane, cyclosporine, liposomal daunorubicin, Edwina-asparaginase,strontium 89, casopitant, netupitant, an NK-1 receptor antagonist,palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide,lorazepam, alprazolam, haloperidol, droperidol, dronabinol,dexamethasone, methylprednisolone, prochlorperazine, granisetron,ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin,epoetin alfa, darbepoetin alfa and mixtures thereof.

The term “anti-HIV agent” or “additional anti-HIV agent” includes, forexample, nucleoside reverse transcriptase inhibitors (NRTI), othernon-nucloeoside reverse transcriptase inhibitors (i.e., those which arenot representative of the present disclosure), protease inhibitors,fusion inhibitors, among others, exemplary compounds of which mayinclude, for example, 3TC (Lamivudine), AZT (Zidovudine), (−)-FTC, ddI(Didanosine), ddC (zalcitabine), abacavir (ABC), tenofovir (PMPA),D-D4FC (Reverset), D4T (Stavudine), Racivir, L-FddC, L-FD4C, NVP(Nevirapine), DLV (Delavirdine), EFV (Efavirenz), SQVM (Saquinavirmesylate), RTV (Ritonavir), IDV (Indinavir), SQV (Saquinavir), NFV(Nelfinavir), APV (Amprenavir), LPV (Lopinavir), fusion inhibitors suchas T20, among others, fuseon and mixtures thereof, including anti-HIVcompounds presently in clinical trials or in development.

Other anti-HIV agents which may be used in coadministration withcompounds according to the present disclosure include, for example,other NNRTI's (i.e., other than the NNRTI's according to the presentdisclosure) may be selected from the group consisting of nevirapine(BI-R6-587), delavirdine (U-90152S/T), efavirenz (DMP-266), UC-781(N-[4-chloro-3-(3-methyl-2-butenyloxy)phenyl]-2methyl3-furancarbothiamide),etravirine (TMC125), Trovirdine (Ly300046.HCl), MKC-442 (emivirine,coactinon), HI-236, HI-240, HI-280, HI-281, rilpivirine (TMC-278),MSC-127, HBY 097, DMP266, Baicalin (TJN-151) ADAM-II (Methyl3′,3′-dichloro-4′,4″-dimethoxy-5′,5″-bis(methoxycarbonyl)-6,6-diphenylhexenoate),Methyl3-Bromo-5-(1-5-bromo-4-methoxy-3-(methoxycarbonyl)phenyl)hept-1-enyl)-2-methoxybenzoate(Alkenyldiarylmethane analog, Adam analog),(5-chloro-3-(phenylsulfinyl)-2′-indolecarboxamide), AAP-BHAP (U-104489or PNU-104489), Capravirine (AG-1549, S-1153), atevirdine (U-87201E),aurin tricarboxylic acid (SD-095345),1-[(6-cyano-2-indolyl)carbonyl]-4-[3-(isopropylamino)-2-pyridinyl]piperazine,1-[5-[[N-(methyl)methylsulfonylamino]-2-indolylcarbonyl-4-[3-(isopropylamino)-2-pyridinyl]piperazine,1-[3-(Ethylamino)-2-[pyridinyl]-4-[(5-hydroxy-2-indolyl)carbonyl]piperazine,1-[(6-Formyl-2-indolyl)carbonyl]-4-[3-(isopropylamino)-2-pyridinyl]piperazine,1-[[5-(Methylsulfonyloxy)-2-indoyly)carbonyl]-4-[3-(isopropylamino)-2-pyridinyl]piperazine,U88204E, Bis(2-nitrophenyl)sulfone (NSC 633001), Calanolide A(NSC675451), Calanolide B,6-Benzyl-5-methyl-2-(cyclohexyloxy)pyrimidin-4-one (DABO-546), DPC 961,E-EBU, E-EBU-dm, E-EPSeU, E-EPU, Foscarnet (Foscavir), HEPT(1-[(2-Hydroxyethoxy)methyl]-6-(phenylthio)thymine), HEPT-M(1-[(2-Hydroxyethoxy)methyl]-6-(3-methylphenyl)thio)thymine),HEPT-S(1-[(2-Hydroxyethoxy)methyl]-6-(phenylthio)-2-thiothymine),Inophyllum P, L-737,126, Michellamine A (NSC650898), Michellamine B(NSC649324), Michellamine F,6-(3,5-Dimethylbenzyl)-1-[(2-hydroxyethoxy)methyl]-5-isopropyluracil,6-(3,5-Dimethylbenzyl)-1-(ethyoxymethyl)-5-isopropyluracil, NPPS, E-BPTU(NSC 648400), Oltipraz(4-Methyl-5-(pyrazinyl)-3H-1,2-dithiole-3-thione),N-{2-(2-Chloro-6-fluorophenethyl]-N′-(2-thiazolyl)thiourea (PETT Cl, Fderivative),N-{2-(2,6-Difluorophenethyl]-N′-[2-(5-bromopyridyl)]thiourea {PETTderivative),N-{2-(2,6-Difluorophenethyl]-N′-[2-(5-methylpyridyl)]thiourea {PETTPyridyl derivative),N-[2-(3-Fluorofuranyl)ethyl]-N′-[2-(5-chloropyridyl)]thiourea,N-[2-(2-Fluoro-6-ethoxyphenethyl)]-N′-[2-(5-bromopyridyl)]thiourea,N-(2-Phenethyl)-N′-(2-thiazolyl)thiourea (LY-73497), L-697,639,L-697,593, L-697,661,3-[2-(4,7-Difluorobenzoxazol-2-yl)ethyl}-5-ethyl-6-methyl(pypridin-2(1H)-thione(2-Pyridinone Derivative),3-[[(2-Methoxy-5,6-dimethyl-3-pyridyl)methyl]amine]-5-ethyl-6-methyl(pypridin-2(1H)-thione,R82150, R82913, R87232, R88703, R89439 (Loviride), R90385, S-2720,Suramin Sodium, TBZ (Thiazolobenzimidazole, NSC 625487),Thiazoloisoindol-5-one,(+)(R)-9b-(3,5-Dimethylphenyl-2,3-dihydrothiazolo[2,3-a]isoindol-5(9bH)-one,Tivirapine (R86183), UC-38 and UC-84, among others.

The term “pharmaceutically acceptable salt” is used throughout thespecification to describe, where applicable, a salt form of one or moreof the compounds described herein which are presented to increase thesolubility of the compound in the gastic juices of the patient'sgastrointestinal tract in order to promote dissolution and thebioavailability of the compounds. Pharmaceutically acceptable saltsinclude those derived from pharmaceutically acceptable inorganic ororganic bases and acids, where applicable. Suitable salts include thosederived from alkali metals such as potassium and sodium, alkaline earthmetals such as calcium, magnesium and ammonium salts, among numerousother acids and bases well known in the pharmaceutical art. Sodium andpotassium salts are particularly preferred as neutralization salts ofthe phosphates according to the present disclosure.

The term “pharmaceutically acceptable derivative” is used throughout thespecification to describe any pharmaceutically acceptable prodrug form(such as an ester, amide other prodrug group), which, uponadministration to a patient, provides directly or indirectly the presentcompound or an active metabolite of the present compound.

General Synthetic Approach

The synthetic realization and optimization of the bifunctional moleculesas described herein may be approached in a step-wise or modular fashion.For example, identification of compounds that bind to the targetmolecules can involve high or medium throughput screening campaigns ifno suitable ligands are immediately available. It is not unusual forinitial ligands to require iterative design and optimization cycles toimprove suboptimal aspects as identified by data from suitable in vitroand pharmacological and/or ADMET assays. Part of the optimization/SARcampaign would be to probe positions of the ligand that are tolerant ofsubstitution and that might be suitable places on which to attach thelinker chemistry previously referred to herein. Where crystallographicor NMR structural data are available, these can be used to focus such asynthetic effort.

In a very analogous way, one can identify and optimize ligands for an E3Ligase, i.e. ULMs/ILMs/VLMs/CLMs/ILMs.

With PTMs and ULMs (e.g. ILMs, VLMs, CLMs, and/or ILMs) in hand, oneskilled in the art can use known synthetic methods for their combinationwith or without a linker moiety. Linker moieties can be synthesized witha range of compositions, lengths and flexibility and functionalized suchthat the PTM and ULM groups can be attached sequentially to distal endsof the linker. Thus a library of bifunctional molecules can be realizedand profiled in in vitro and in vivo pharmacological and ADMET/PKstudies. As with the PTM and ULM groups, the final bifunctionalmolecules can be subject to iterative design and optimization cycles inorder to identify molecules with desirable properties.

Compounds of the present disclosure [e.g., the general Formula PTM-I]may be prepared by methods known in the art of organic synthesis as setforth in the specific Examples described in this application. In all ofthe methods, it is well understood that protecting groups for sensitiveor reactive groups may be employed where necessary in accordance withgeneral principles of chemistry. Protecting groups are manipulatedaccording to standard methods of organic synthesis (T. W. Green and P.G. M. Wuts (1999) Protective Groups in Organic Synthesis, 3^(rd)edition, John Wiley & Sons). These groups are removed at a convenientstage of the compound synthesis using methods that are readily apparentto those skilled in the art. The selection of processes as well as thereaction conditions and order of their execution shall be consistentwith the preparation of compounds of the present disclosure, includingcompounds of Formula PTM-I. Schemes described below illustrate thegeneral methods of preparing compounds with the structure featured asFormula PTM-I.

Example Synthesis of Exemplary Compound 104 Step 1. The Synthesis of1-bromo-4-(5-bromopentyloxy)benzene (2)

To a solution of 4-bromophenol (3.0 g, 17.4 mmol) in ethanol (20 mL) wasadded potassium carbonate (3.6 g, 26.2 mmol) and 1,5-dibromopentane (6.6g, 28.7 mmol). The mixture was heated to 80° C. for 16 hours undernitrogen. After cooling to room temperature, the mixture was extractedwith ethyl acetate (20 mL×3). The combined organic phase was dried overanhydrous sodium sulfate, filtered, and concentrated in vacuo andpurified by silica gel (petroleum ether/ethyl acetate=50:1) to givecompound 1-bromo-4-(6-bromohexyloxy)benzene (4.52 g, 80% yield) as awhite solid.

Step 2. The synthesis of methyl2-(3-(5-(4-bromophenoxy)pentyloxy)isoxazol-5-yl)-3-methylbutanoate (3)

To a solution of 1-bromo-4-(5-bromopentyloxy)benzene (1.4 g, 4.3 mmol)in N,N-dimethylformamide (10 mL) was added methyl2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoate (700 mg, 4.4 mmol) andpotassium carbonate (1.4 g, 10.5 mmol). The mixture was stirred at roomtemperature overnight. Water (15 mL) was added to the reaction mixture,and extracted with ethyl acetate (15 mL×3). The organic layer was washedwith brine (15 mL×3). The combined organic phases were dried overanhydrous sodium sulfate and concentrated in vacuo and purified byPre-TLC (petroether/ethyl acetate=10:1) to give compound methyl2-(3-(5-(4-bromophenoxy)pentyloxy)isoxazol-5-yl)-3-methylbutanoate (300mg, 20% yield) as light oil.

LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (30 mm×4.6mm×3.5 μm); Column Temperature: 40° C.; Flow Rate: 2.0 mL/min; MobilePhase: from 90% [water+10 mM NH₄HCO₃] and 10% [CH₃CN] to 5% [water+10 mMNH₄HCO₃] and 95% [CH₃CN] in 0.5 min, then under this condition for 1.5min, finally changed to 90% [water+10 mM NH₄HCO₃] and 10% [CH₃CN] in 0.1min and under this condition for 0.5 min). Purity is 63.97%, Rt=1.387min.; MS Calcd.: 440.33; MS Found: 440.0 [M+H]⁺.

Step 3. The synthesis of methyl3-methyl-2-(3-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pentyloxy)isoxazol-5-yl)butanoate(4)

To a solution of methyl2-(3-(5-(4-bromophenoxy)pentyloxy)isoxazol-5-yl)-3-methylbutanoate (200mg, 0.46 mmol) in 1,2-Dimethoxyethane (10 mL) was added4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (278 mg, 1.1mmol), potassium acetate (129 mg, 1.3 mmol) and[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (65 mg, 0.10mmol). The reaction mixture was stirred at 80° C. overnight undernitrogen. Water (10 mL) was added to the mixture and extracted withethyl acetate (5 mL×3). The combined organic layer was washed with brine(10 mL×2), dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo and purified by pre-TLC (petroether/ethylacetate=10:1) to give methyl3-methyl-2-(3-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pentyloxy)isoxazol-5-yl)butanoate(110 mg, 50% yield) as light oil.

Step 4. The synthesis of methyl2-(3-(5-(3′-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methylcarbamoyl)-5′-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4′-methylbiphenyl-4-yloxy)pentyloxy)isoxazol-5-yl)-3-methylbutanoate(5)

To a solution of methyl3-methyl-2-(3-(6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)hexyloxy)isoxazol-5-yl)butanoate(200 mg, 0.41 mmol) and5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamide(220 mg, 0.45 mmol) in dioxane (5 mL) and H₂O (0.5 mL) was added cesiumcarbonate (450 mg, 1.38 mmol), Tri-tert-butylphosphine tetrafluoroborate(40 mg, 0.14 mmol),[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (46 mg, 0.06mmol), stirred at 100° C. for 2 hours under nitrogen. The mixture wasquenched with water (10 mL) and extracted with dichloromethane/methanol(10:1) (10 mL×3), and the combined organic layer was washed with brine(5 mL×2), dried over anhydrous sodium sulfate, filtered and concentratedin vacuo and purified by pre-TLC (dichloromethane/methanol=15:1) to givemethyl2-(3-(5-(3′-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methylcarbamoyl)-5′-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4′-methylbiphenyl-4-yloxy)pentyloxy)isoxazol-5-yl)-3-methylbutanoate(110 mg, 36% yield) as a yellow solid.

LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50 mm×4.6mm×3.5 μm); Column Temperature: 40° C.; Flow Rate: 2.0 mL/min; MobilePhase: from 90% [(total 10 mM AcONH₄) water/CH₃CN=900/100 (v/v)] and 10%[(total 10 mM AcONH₄) water/CH₃CN=100/900 (v/v)] to 10% [(total 10 mMAcONH₄) water/CH₃CN=900/100 (v/v)] and 90% [(total 10 mM AcONH₄)water/CH₃CN=100/900 (v/v)] in 1.6 min, then under this condition for 2.4min, finally changed to 90% [(total 10 mM AcONH₄) water/CH₃CN=900/100(v/v)] and 10% [(total 10 mM AcONH₄) water/CH₃CN=100/900 (v/v)] in 0.1min and under this condition for 0.7 min). Purity is 76.61%, Rt=1.275min.; MS Calcd.: 756.93; MS Found: 757.3[M+H]⁺.

Step 5. The synthesis of2-(3-(5-(3′-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methylcarbamoyl)-5′-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4′-methylbiphenyl-4-yloxy)pentyloxy)isoxazol-5-yl)-3-methylbutanoicacid (6)

To a solution of methyl2-(3-(5-(3′-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methylcarbamoyl)-5′-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4′-methylbiphenyl-4-yloxy)pentyloxy)isoxazol-5-yl)-3-methylbutanoate(110 mg, 0.115 mmol) dissolved in methanol (5 mL) was added lithiumhydroxide (40 mg, 1.6 mmol), and heated to 80° C. for 3 h. The reactionmixture solvent was concentrated in vacuo, water was added to themixture and neutralized by hydrochloric acid (1 M), then extracted withethyl acetate (5 mL×3). The combined organic phases were dried overanhydrous sodium sulfate, filtered, and concentrated in vacuo andpurified by pre-TLC (dichloromethane/methanol=10:1) to give compound2-(3-(5-(3′-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methylcarbamoyl)-5′-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4′-methylbiphenyl-4-yloxy)pentyloxy)isoxazol-5-yl)-3-methylbutanoicacid (80 mg, 74% yield) as pale yellow oil.

LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (30 mm×4.6mm×3.5 μm); Column Temperature: 40° C.; Flow Rate: 2.0 mL/min; MobilePhase: from 90% [water+10 mM NH₄HCO₃] and 10% [CH₃CN] to 5% [water+10 mMNH₄HCO₃] and 95% [CH₃CN] in 0.5 min, then under this condition for 1.5min, finally changed to 90% [water+10 mM NH₄HCO₃] and 10% [CH₃CN] in 0.1min and under this condition for 0.5 min.). Purity is 72.34%, Rt=0.946min.; MS Calcd.: 742.90; MS Found: 743.3[M+H]⁺.

Step 6. The synthesis of(2S,4R)-1-(2-(3-(5-(3′-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methylcarbamoyl)-5′-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4′-methylbiphenyl-4-yloxy)pentyloxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide(Compound 104)

To a solution of2-(3-(5-(3′-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methylcarbamoyl)-5′-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4′-methylbiphenyl-4-yloxy)pentyloxy)isoxazol-5-yl)-3-methylbutanoicacid (80 mg, 0.1 mmol),(2S,4R)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide(40 mg, 0.12 mmol) in N,N-dimethylformamide (2 mL) was added HATU (46mg, 1.12 mmol) and ethyldiisopropylamine (40 mg, 0.3 mmol), and stirredat room temperature for 5 hours. The reaction mixture was quenched withwater (5.0 mL) and extracted with dichloromethane/methanol=10:1 (5mL×3). The organic layer was washed with brine (10 mL×2). The combinedorganic phases were dried over anhydrous sodium sulfate, filtered,concentrated in vacuo and purified by pre-HPLC to give(2S,4R)-1-(2-(3-(5-(3′-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methylcarbamoyl)-5′-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4′-methylbiphenyl-4-yloxy)pentyloxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide(32 mg, 28% yield) as pale yellow solid.

LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50 mm×4.6mm×3.5 μm); Column Temperature: 40° C.; Flow Rate: 2.0 mL/min; MobilePhase: from 95% [water+10 mM NH₄HCO₃] and 5% [CH₃CN] to 0% [water+10 mMNH₄HCO₃] and 100% [CH₃CN] in 3.0 min, then under this condition for 1.0min, finally changed to 95% [water+10 mM NH₄HCO₃] and 5% [CH₃CN] in 0.1min and under this condition for 0.7 min). Purity is 98.28%, Rt=2.796min; MS/2 Calcd.: 1056.32; MS Found: 1057.4 [M+H]⁺.

HPLC (Agilent HPLC 1200, Column: Waters X-Bridge C18 (150 mm×4.6 mm×3.5m); Column Temperature: 40° C.; Flow Rate: 1.0 mL/min; Mobile Phase:from 95% [water+10 mM NH₄HCO₃] and 5% [CH₃CN] to 0% [water+10 mMNH₄HCO₃] and 100% [CH₃CN] in 10 min, then under this condition for 5min, finally changed to 95% [water+10 mM NH₄HCO₃] and 5% [CH₃CN] in 0.1min and under this condition for 5 min). Purity is 91.56%, Rt=9.494 min.

¹H NMR (400 MHz, CDCl₃) δ 0.86-0.88 (6H, m), 1.01-1.03 (3H, m),1.35-1.42 (4H, m), 1.63-1.69 (5H, brs), 1.82-1.84 (4H, brs), 1.95-1.98(1H, m), 2.12-2.19 (3H, m), 2.34 (3H, d, J=5.6 Hz), 2.40-2.41 (4H, m),2.52 (3H, d, J=3.2 Hz), 2.88 (1H, s), 2.96 (1H, s), 2.97-3.11 (3H, m),3.28-3.34 (2H, m), 3.44-3.66 (3H, m), 3.70 (1H, s), 3.78-4.03 (5H, m),4.18-4.23 (2H, m), 4.36-4.50 (1H, m), 4.56-4.79 (3H, m), 4.93-5.07 (1H,m), 5.81 (1H, d, J=9.6 Hz), 5.91 (1H, d, J=14.4 Hz), 6.90 (2H, d, J=8.0Hz), 7.06-7.21 (2H, m), 7.27-7.41 (8H, m), 7.79-8.01 (1H, m), 8.67 (1H,d, J=2.8 Hz).

Chemical Formula: C₅₉H₇₃N₇O₉S, Molecular Weight: 1056.32.

Total H count from HNMR data: 73.

Example Synthesis of Exemplary Compound 107 Step 1. The synthesis ofmethyl 2-(3-(4-(4-bromophenoxy)butoxy)isoxazol-5-yl)-3-methylbutanoate

A mixture of 1-bromo-4-(4-bromobutoxy)benzene (200 mg, 0.65 mmol),methyl 2-(6-hydroxy-1-oxoisoindolin-2-yl)-3-methylbutanoate (130 mg,0.65 mmol) and potassium carbonate (176 mg, 1.3 mmol) inN,N-dimethylformamide (5 mL) was stirred at 30° C. overnight. Aftercooling, it was diluted with water (20 mL) and extracted with ethylacetate (10 mL×3). The combined organic layers were washed by brine (20mL), dried over anhydrous sodium sulfate, filtered and concentrated invacuo. The residue was purified by column chromatography on silica(petroleum ether/ethyl acetate=5/1) to give methyl2-(3-(4-(4-bromophenoxy)butoxy)isoxazol-5-yl)-3-methylbutanoate (240 mg,87% yield) as yellow oil.

LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (30 mm×4.6mm×3.5 μm); Column Temperature: 40° C.; Flow Rate: 1.5 mL/min; MobilePhase: from 90% [water+10 mM NH₄HCO₃] and 10% [CH₃CN] to 5% [water+10 mMNH₄HCO₃] and 95% [CH₃CN] in 0.5 min, then under this condition for 1.5min, finally changed to 90% [water+10 mM NH₄HCO₃] and 10% [CH₃CN] in 0.1min and under this condition for 0.5 min). Purity is 96.96%, Rt=1.718min; MS Calcd.: 425.1; MS Found: 426.8 [M+H]⁺.

Step 2. The synthesis of methyl3-methyl-2-(3-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)butoxy)isoxazol-5-yl)butanoate

A mixture of methyl2-(3-(4-(4-bromophenoxy)butoxy)isoxazol-5-yl)-3-methylbutanoate (240 mg,0.56 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)(24 mg, 0.03 mmol), bis(pinacolato)diboron (571.8 mg, 2.25 mmol) andpotassium acetate (164.8 mg, 1.68 mmol) in dimethoxyethane (5 mL) wasstirred at 80° C. for 3 hours under nitrogen. After cooling, it wasdiluted with water (20 mL) and extracted with ethyl acetate (10 mL×3).The combined organic layers were washed by brine (20 mL), dried overanhydrous sodium sulfate, filtered and concentrated in vacuo. Theresidue was purified by column chromatography on silica (petroleumether/ethyl acetate=2/1) to give methyl3-methyl-2-(3-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)butoxy)isoxazol-5-yl)butanoate(120 mg, 45% yield) as yellow oil.

LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (30 mm×4.6mm×3.5 μm); Column Temperature: 40° C.; Flow Rate: 2.0 mL/min; MobilePhase: from 90% [water+10 mM NH₄HCO₃] and 10% [CH₃CN] to 5% [water+10 mMNH₄HCO₃] and 95% [CH₃CN] in 0.5 min, then under this condition for 1.5min, finally changed to 90% [water+10 mM NH₄HCO₃] and 10% [CH₃CN] in 0.1min and under this condition for 0.5 min). Purity is 70.55%, Rt=1.383min; MS Calcd.: 473.3; MS Found: 474.3 [M+H]⁺.

Step 3. The synthesis of methyl2-(3-(4-(3′-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methylcarbamoyl)-5′-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4′-methylbiphenyl-4-yloxy)butoxy)isoxazol-5-yl)-3-methylbutanoate

A mixture of methyl3-methyl-2-(3-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)butoxy)isoxazol-5-yl)butanoate(120 mg, 0.25 mmol),5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamide(120 mg, 0.25 mmol), cesium carbonate (203 mg, 0.63 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (12 mg, 0.02mmol) and tri-tert-butylphosphine tetrafluoroborate (24 mg, 0.08 mmol)in 1,4-dioxane/water (5 mL, v/v=10/1) was stirred at 100° C. for 5 hoursunder nitrogen. After cooling, it was diluted with water (15 mL) andextracted with dichloromethane (10 mL×3). The combined organic layerswere washed by brine (20 mL), dried over anhydrous sodium sulfate,filtered and concentrated in vacuo. The residue was purified byPrep-HPLC to give methyl2-(3-(4-(3′-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methylcarbamoyl)-5′-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4′-methylbiphenyl-4-yloxy)butoxy)isoxazol-5-yl)-3-methylbutanoate(45 mg, 24% yield) as a white solid.

Step 4. The synthesis of2-(3-(4-(3′-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methylcarbamoyl)-5′-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4′-methylbiphenyl-4-yloxy)butoxy)isoxazol-5-yl)-3-methylbutanoicacid

To a solution of methyl2-(3-(4-(3′-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methylcarbamoyl)-5′-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4′-methylbiphenyl-4-yloxy)butoxy)isoxazol-5-yl)-3-methylbutanoate(45 mg, 0.06 mmol) in methanol (2 mL) was added lithium hydroxidehydrate (13 mg, 0.30 mmol) and water (1 mL), then it was stirred at 85°C. for 30 minutes. After cooling, the reaction mixture was diluted bywater (10 mL) and extracted by dichloromethane (20 mL×3). The combinedorganic layers were washed by brine (20 mL), dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo. The residue was purified byPrep-TLC to give2-(3-(4-(3′-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methylcarbamoyl)-5′-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4′-methylbiphenyl-4-yloxy)butoxy)isoxazol-5-yl)-3-methylbutanoicacid (40 mg, 91% yield) as a white solid.

LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50 mm×4.6mm×3.5 μm); Column Temperature: 40° C.; Flow Rate: 2.0 mL/min; MobilePhase: from 95% [water+10 mM NH₄HCO₃] and 5% [CH₃CN] to 0% [water+10 mMNH₄HCO₃] and 100% [CH₃CN] in 1.6 min, then under this condition for 1.4min, finally changed to 95% [water+10 mM NH₄HCO₃] and 5% [CH₃CN] in 0.1min and under this condition for 0.7 min). Purity is 85.58%, Rt=1.555min; MS Calcd.: 728.4; MS Found: 729.4 [M+H]⁺.

Step 5. The synthesis of(2S,4R)-1-(2-(3-(4-(3′-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methylcarbamoyl)-5′-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4′-methylbiphenyl-4-yloxy)butoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

A mixture of2-(3-(4-(3′-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methylcarbamoyl)-5′-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4′-methylbiphenyl-4-yloxy)butoxy)isoxazol-5-yl)-3-methylbutanoicacid (40 mg, 0.06 mmol),(2S,4R)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide(18 mg, 0.06 mmol),0-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluroniumhexamluorophosphate (30 mg, 0.08 mmol) and ethyldiisopropylamine (14 mg,0.11 mmol) in N,N-dimethylformamide (2 mL) was stirred at roomtemperature for an hour. It was diluted with water (10 mL) and extractedwith dichloromethane (10 mL×3). The combined organic layers were washedby brine (10 mL), dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. The residue was purified by Prep-HPLC to give(2S,4R)-1-(2-(3-(4-(3′-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methylcarbamoyl)-5′-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4′-methylbiphenyl-4-yloxy)butoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide(15 mg, 26% yield) as a white solid.

LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50 mm×4.6mm×3.5 μm); Column Temperature: 40° C.; Flow Rate: 2.0 mL/min; MobilePhase: from 95% [water+10 mM NH₄HCO₃] and 5% [CH₃CN] to 0% [water+10 mMNH₄HCO₃] and 100% [CH₃CN] in 3.0 min, then under this condition for 1.0min, finally changed to 95% [water+10 mM NH₄HCO₃] and 5% [CH₃CN] in 0.1min and under this condition for 0.7 min). Purity is 96.77%, Rt=2.714min; MS Calcd.: 1041.5; MS Found: 1042.4 [M+H]⁺.

HPLC (Agilent HPLC 1200, Column: Waters X-Bridge C18 (150 mm×4.6 mm×3.5μm); Column Temperature: 40° C.; Flow Rate: 1.0 mL/min; Mobile Phase:from 95% [water+10 mM NH₄HCO₃] and 5% [CH₃CN] to 0% [water+10 mMNH₄HCO₃] and 100% [CH₃CN] in 10 min, then under this condition for 5min, finally changed to 95% [water+10 mM NH₄HCO₃] and 5% [CH₃CN] in 0.1min and under this condition for 5 min). Purity is 94.25%, Rt=9.196 min.

¹H NMR (400 MHz, CDCl₃) δ 0.89-0.91 (3H, m), 1.01-1.04 (3H, m),1.26-1.43 (6H, m), 1.66 (6H, m), 1.95-1.98 (5H, m), 2.13-2.19 (3H, m),2.33-2.35 (3H, m), 2.40-2.41 (3H, m), 2.51-2.52 (3H, m), 3.00-3.11 (4H,m), 3.29-3.34 (2H, m), 3.51-3.64 (3H, m), 3.93-4.05 (4H, m), 4.27 (2H,m), 4.32-4.50 (1H, m), 4.57-4.80 (3H, m), 4.92-5.08 (1H, m), 5.80-5.94(2H, m), 6.89-6.91 (2H, m), 7.12-7.18 (2H, m), 7.28-7.44 (8H, m),7.53-7.83 (1H, m), 8.67 (1H, m).

Chemical Formula: C₅₈H₇₁N₇O₉S, Molecular Weight: 1042.29.

Total H count from HNMR data: 71.

Example Synthesis of Exemplary Compound 99 Step 1. The Synthesis of2-(4-bromobenzyloxy)ethanol

To the solution of ethylene glycol (1.0 g, 16.1 mmol) in tetrahydrofuran(20 mL) was added sodium hydride (1.3 g, 32.2 mmol, 60% in mineral oil)at room temperature and the mixture was stirred for 30 minutes. To themixture above was added a solution of 1-bromo-4-(bromomethyl)benzene(400 mg, 1.6 mmol) in tetrahydrofuran (10 mL) and the reaction mixturewas refluxed overnight. After cooling to room temperature, the mixturewas poured into saturated ammonium chloride (30 mL) and extracted withdichloromethane (30 mL×3). The organic phase was concentrated in vacuoand the residue was purified by silica gel(dichloromethane/methanol=20/1) to give 2-(4-bromobenzyloxy)ethanol (221mg, 60% yield) as colorless oil.

Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50 mm*4.6 mm*3.5m); Column Temperature: 40° C.; Flow Rate: 2.0 mL/min; Mobile Phase:from 95% [water+10 mM NH₄HCO₃] and 5% [CH₃CN] to 0% [water+10 mMNH₄HCO₃] and 100% [CH₃CN] in 3.0 min, then under this condition for 1.0min, finally changed to 95% [water+10 mM NH₄HCO₃] and 5% [CH₃CN] in 0.1min and under this condition for 0.7 min. Purity is 88.9%, Rt=1.588 min;MS Calcd.: 229.9; MS Found: 248.2 [M+NH₄]⁺.

Chemical Formula: C₁₃H₁₉Br₂O₂, Molecular Weight: 231.09.

Route for methyl(S)-2-(6-hydroxy-1-oxoisoindolin-2-yl)-3-methylbutanoate

Step 2. The synthesis of methyl 5-hydroxy-2-methylbenzoate

To a solution of 5-hydroxy-2-methylbenzoic acid (10.0 g, 65.7 mmol) inmethanol (200 mL) was added thionyl chloride (5 mL). After stirred at85° C. for 5 hours, the solvent was removed in vacuo to give methyl5-hydroxy-2-methylbenzoate (10.9 g, 100% yield) as a pale yellow solid,which was used to next step without further purification.

LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (30 mm×3mm×2.5 μm); Column Temperature: 40° C.; Flow Rate: 1.5 mL/min; MobilePhase: from 95% [water+10 mM NH₄HCO₃] and 5% [CH₃CN+10 mM NH₄HCO₃] to 5%[water+10 mM NH₄HCO₃] and 95% [CH₃CN+10 mM NH₄HCO₃] in 1.5 min, thenunder this condition for 0.5 min, finally changed to 95% [water+10 mMNH₄HCO₃] and 5% [CH₃CN+10 mM NH₄HCO₃] in 0.1 min and under thiscondition for 0.5 min). Purity is 98.56%, Rt=1.052 min; MS Calcd.:166.1; MS Found: 167.1 [M+H]⁺.

Step 3. The synthesis of methyl5-(tert-butyldimethylsilyloxy)-2-methylbenzoate

To a solution of methyl 5-hydroxy-2-methylbenzoate (10.9 g, 65.7 mmol)in N,N-dimethylformamide (100 mL) was added imidazole (8.95 g, 131 mmol)and tert-butyldimethylsilyl chloride (11.9 g, 78.8 mmol) at 0° C., andthe mixture was agitated at 0° C. for 1 hour. The mixture was warmed upto room temperature for overnight. The reaction mixture was added to icewater (200 mL), and extracted with ethyl acetate (100 mL×3). The organiclayer was washed with cold water (50 mL) and brine (50 mL). The combinedorganic phases were dried over anhydrous sodium sulfate, filtered, andconcentrated in vacuo to give methyl5-(tert-butyldimethylsilyloxy)-2-methylbenzoate (12.0 g, 65%) as paleyellow oil, and used to next step without further purification.

Step 4. The synthesis of methyl2-(bromomethyl)-5-(tert-butyldimethylsilyloxy)benzoate

To a solution of compound methyl5-(tert-butyldimethylsilyloxy)-2-methylbenzoate (11.0 g, 39.2 mmol) incarbon tetrachloride (120 mL) was added 1-bromopyrrolidine-2,5-dione(6.98 g, 39.2 mmol) and benzoyl peroxide (0.475 g, 1.96 mmol). After thereaction mixture was heated to 70° C. for 3 hours. The reaction mixturewas cooled down and washed by sodium sulfite solution (100 mL×2, 50%saturated concentration), water (100 mL) and brine (100 mL). The organiclayer was dried over anhydrous sodium sulfate, filtered, andconcentrated in vacuo to give methyl2-(bromomethyl)-5-(tert-butyldimethylsilyloxy)benzoate (14.1 g, 100%) aslight brown oil, and used to next step without further purification

LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (30 mm×3mm×2.5 μm); Column Temperature: 40° C.; Flow Rate: 1.5 mL/min; MobilePhase: from 95% [water+10 mM NH₄HCO₃] and 5% [CH₃CN+10 mM NH₄HCO₃] to 5%[water+10 mM NH₄HCO₃] and 95% [CH₃CN+10 mM NH₄HCO₃] in 1.5 min, thenunder this condition for 0.5 min, finally changed to 95% [water+10 mMNH₄HCO₃] and 5% [CH₃CN+10 mM NH₄HCO₃] in 0.1 min and under thiscondition for 0.5 min). Purity is 69.62%, Rt=1.820 min; MS Calcd.:358.1; MS Found: 279.1 [M−Br+H]⁺.

Step 5. The synthesis of (S)-methyl2-(6-(tert-butyldimethylsilyloxy)-1-oxoisoindolin-2-yl)-3-methylbutanoate

To a solution of methyl2-(bromomethyl)-5-(tert-butyldimethylsilyloxy)benzoate (14.1 g, 39.2mmol) in acetonitrile (150 mL) was added (S)-methyl2-amino-3-methylbutanoate hydrochloride (6.57 g, 39.2 mmol). To themixture was added ethyldiisopropylamine (10.1 g, 78.4 mmol) through anaddition funnel over 10 minutes and the mixture was stirred at roomtemperature for 1 hour before heating to 40° C. overnight. The reactionmixture was concentrated in vacuo. The residue was stirred in ethylacetate (200 mL) and washed with hydrochloric acid (1N, 50 mL), sodiumbicarbonate (sat. 50 mL) and brine (50 mL). The organic layers was driedover anhydrous sodium sulfate, filtered, and concentrated in vacuo togive crude (S)-methyl2-(6-(tert-butyldimethylsilyloxy)-1-oxoisoindolin-2-yl)-3-methylbutanoate(13.0 g, 88%) as brown oil, and used to next step without furtherpurification.

Step 6. The synthesis of (S)-methyl2-(6-hydroxy-1-oxoisoindolin-2-yl)-3-methylbutanoate

To a stirred cold solution of (S)-methyl2-(6-(tert-butyldimethylsilyloxy)-1-oxoisoindolin-2-yl)-3-methylbutanoate(13.0 g, 34.4 mmol) in N,N-dimethylformamide (50 mL) and water (5 mL),was added potassium carbonate (9.50 g, 68.9 mmol) by portions over 5minutes. The resulting reaction mixture was stirred at room temperaturefor 1 hour. The reaction mixture was cooled in an ice bath. To themixture, hydrochloric acid (12M, 43.1 mmol) was added slowly. After theaddition, acetonitrile (100 mL) was added to the mixture and stirred atroom temperature for 10 minutes and filtered. The filtrate wasconcentrated and purified by silica gel (petroether/ethyl acetate=2:1)to give (S)-methyl 2-(6-hydroxy-1-oxoisoindolin-2-yl)-3-methylbutanoate(6.60 g, 73%) as a pale yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ 0.81 (3H, d, J=6.8 Hz), 0.97 (3H, d, J=6.8Hz), 2.23-2.33 (1H, m), 3.66 (3H, s), 4.37-4.47 (2H, m), 4.55 (1H, d,J=10.4 Hz), 7.02-7.04 (2H, m), 7.40-7.42 (1H, m), 9.82 (1H, s).

Chemical Formula: C₁₄H₁₇NO₄, Molecular Weight: 263.29

Total H count from HNMR data: 17.

Step 7. The synthesis of (S)-methyl2-(6-(2-(4-bromobenzyloxy)ethoxy)-1-oxoisoindolin-2-yl)-3-methylbutanoate

To the mixture of 2-(4-bromobenzyloxy)ethanol (100 mg, 0.43 mmol),(S)-methyl 2-(6-hydroxy-1-oxoisoindolin-2-yl)-3-methylbutanoate (113 mg,0.43 mmol), triphenylphosphine (113 mg, 0.43 mmol) and triethylamine (43mg, 0.43 mmol) in dry tetrahydrofuran (10 mL) was added diethylazodicarboxylate (75 mg, 0.43 mmol) at room temperature under nitrogenatmosphere and the mixture was stirred for 2 hours. The mixture wasconcentrated in vacuo and the residue was purified by silica gel(petroleum ether/ethyl acetate=10/1) to give (S)-methyl2-(6-(2-(4-bromobenzyloxy)ethoxy)-1-oxoisoindolin-2-yl)-3-methylbutanoate(133 mg, 65% yield) as yellow oil.

Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50 mm*4.6 mm*3.5m); Column Temperature: 40° C.; Flow Rate: 2.0 mL/min; Mobile Phase:from 95% [water+10 mM NH₄HCO₃] and 5% [CH₃CN] to 0% [water+10 mMNH₄HCO₃] and 100% [CH₃CN] in 3.0 min, then under this condition for 1.0min, finally changed to 95% [water+10 mM NH₄HCO₃] and 5% [CH₃CN] in 0.1min and under this condition for 0.7 min. Purity is 65.4%, Rt=2.085 min;MS Calcd.: 475.1; MS Found: 476.2 [M+H]⁺.

Chemical Formula: C₂₃H₂₆BrNO₅, Molecular Weight: 476.36.

Step 8. The synthesis of (S)-methyl3-methyl-2-(1-oxo-6-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyloxy)ethoxy)isoindolin-2-yl)butanoate

The mixture of (S)-methyl2-(6-(2-(4-bromobenzyloxy)ethoxy)-1-oxoisoindolin-2-yl)-3-methylbutanoate(100 mg, 0.21 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (53 mg, 0.21mmol), 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride (26 mg,0.04 mmol) and potassium carbonate (21 mg, 0.42 mmol) in dioxane (5 mL)was refluxed for 3 hours. The reaction mixture was used for the nextstep directly without further purification.

Step 9. The synthesis of (S)-methyl2-(6-(2-((3′-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methylcarbamoyl)-5′-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4′-methylbiphenyl-4-yl)methoxy)ethoxy)-1-oxoisoindolin-2-yl)-3-methylbutanoate

The mixture of crude (S)-methyl3-methyl-2-(1-oxo-6-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyloxy)ethoxy)isoindolin-2-yl)butanoate(110 mg, 0.21 mmol),5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamide(100 mg, 0.21 mmol), 1,1′-bis(diphenylphosphino)ferrocene palladiumdichloride (26 mg, 0.04 mmol) and cesium carbonate (136 mg, 0.42 mmol)in dioxane/water (5 mL, 10/1) was heated at 100° C. for 5 hours. Aftercooling to room temperature, the mixture was poured into water (30 mL)and extracted with dichloromethane (30 mL×3). The organic phase wasconcentrated in vacuo and the residue was purified by silica gel(dichloromethane/methanol=20/1) to give (S)-methyl2-(6-(2-((3′-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methylcarbamoyl)-5′-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4′-methylbiphenyl-4-yl)methoxy)ethoxy)-1-oxoisoindolin-2-yl)-3-methylbutanoate(83 mg, 50% yield) as brown oil.

Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (30 mm*4.6 mm*3.5μm); Column Temperature: 40° C.; Flow Rate: 2.0 mL/min; Mobile Phase:from 90% [water+10 mM NH₄HCO₃] and 10% [CH₃CN] to 5% [water+10 mMNH₄HCO₃] and 95% [CH₃CN] in 0.5 min, then under this condition for 1.5min, finally changed to 90% [water+10 mM NH₄HCO₃] and 10% [CH₃CN] in 0.1min and under this condition for 0.5 min. Purity is 41.7%, Rt=1.463 min;MS Calcd.: 792.4; MS Found: 794.3 [M+H]⁺.

Chemical Formula: C₄₆H₅₆N₄O₈, Molecular Weight: 792.96.

Step 10. The synthesis of(S)-2-(6-(2-((3′-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methylcarbamoyl)-5′-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4′-methylbiphenyl-4-yl)methoxy)ethoxy)-1-oxoisoindolin-2-yl)-3-methylbutanoicacid

The mixture of (S)-methyl2-(6-(2-((3′-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methylcarbamoyl)-5′-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4′-methylbiphenyl-4-yl)methoxy)ethoxy)-1-oxoisoindolin-2-yl)-3-methylbutanoate(80 mg, 0.1 mmol) and lithium hydroxide monohydrate (42 mg, 1.0 mmol) inmethanol (10 mL) was refluxed for 5 hours. The reaction mixture wasconcentrated in vacuo and the residue was redissolved in water (10 mL).The pH value of solution was adjusted to 5-6 with hydrochloride acid(1.0 N) and extracted with dichloromethane (20 mL×3). The combinedorganic solvent was concentrated and the residue was purified by silicagel (dichloromethane/methanol=20/1) to give(S)-2-(6-(2-((3′-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methylcarbamoyl)-5′-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4′-methylbiphenyl-4-yl)methoxy)ethoxy)-1-oxoisoindolin-2-yl)-3-methylbutanoicacid (62 mg, 80% yield) as a brown solid.

Agilent LCMS 1200-6110, Column: Waters X-Bridge C18 (50 mm*4.6 mm*3.5μm); Column Temperature: 40° C.; Flow Rate: 2.0 mL/min; Mobile Phase:from 95% [water+0.05% TFA] and 5% [CH₃CN+0.05% TFA] to 0% [water+0.05%TFA] and 100% [CH₃CN+0.05% TFA] in 1.6 min, then under this conditionfor 1.4 min, finally changed to 95% [water+0.05% TFA] and 5%[CH₃CN+0.05% TFA] in 0.05 min and under this condition for 0.7 min.Purity is 53.3%, Rt=1.516 min; MS Calcd.: 778.4; MS Found: 779.4 [M+H]⁺.

Chemical Formula: C₂₄H1₉IN₄O₂S, Molecular Weight: 778.93.

Step 11. The synthesis of(2S,4R)-1-((S)-2-(6-(2-((3′-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methylcarbamoyl)-5′-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4′-methylbiphenyl-4-yl)methoxy)ethoxy)-1-oxoisoindolin-2-yl)-3-methylbutanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

The mixture of(S)-2-(6-(2-((3′-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methylcarbamoyl)-5′-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4′-methylbiphenyl-4-yl)methoxy)ethoxy)-1-oxoisoindolin-2-yl)-3-methylbutanoicacid (60 mg, 0.08 mmol),(2S,4R)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide(26 mg, 0.08 mmol),1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (46 mg, 0.12 mmol) and ethyldiisopropylamine(31 mg, 0.24 mmol) in N,N-dimethylformamide (5 mL) was stirred at roomtemperature for 1 hour. The reaction mixture was poured into water (15mL) and extracted with dichloromethane (20 mL×3). The combined organicsolvent was concentrated in vacuo and the residue was purified bypre-HPLC [Gilson-GX281; Column: Waters X-Bridge C18: 100 mm*30 mm 5 m;Mobile Phase: from 65% [water+10 mM NH₄HCO₃] and 35% [CH₃CN] to 45%[water+10 mM NH₄HCO₃] and 55% [CH₃CN] in 8 min, then changed to 5%[water+10 mM NH₄HCO₃] and 95% [CH₃CN] in 0.2 min and under thiscondition for 3.8 min; Flow rate: 20 mL/min; Column temperature: roomtemperature] to give(2S,4R)-1-((S)-2-(6-(2-((3′-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methylcarbamoyl)-5′-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4′-methylbiphenyl-4-yl)methoxy)ethoxy)-1-oxoisoindolin-2-yl)-3-methylbutanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide(70 mg, 80% yield) as a pale yellow solid.

Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50 mm*4.6 mm*3.5m); Column Temperature: 40° C.; Flow Rate: 2.0 mL/min; Mobile Phase:from 95% [water+10 mM NH₄HCO₃] and 5% [CH₃CN] to 0% [water+10 mMNH₄HCO₃] and 100% [CH₃CN] in 3.0 min, then under this condition for 1.0min, finally changed to 95% [water+10 mM NH₄HCO₃] and 5% [CH₃CN] in 0.1min and under this condition for 0.7 min. Purity is 14.0%, Rt=2.604 min;MS Calcd.: 1091.5; MS Found: 547.0 [M/2+H]⁺.

Agilent HPLC 1200, Column: Waters X-Bridge C18 (150 mm*4.6 mm*3.5 m);Column Temperature: 40° C.; Flow Rate: 1.0 mL/min; Mobile Phase: from95% [water+10 mM NH₄HCO₃] and 5% [CH₃CN] to 0% [water+10 mM NH₄HCO₃] and100% [CH₃CN] in 10 min, then under this condition for 5 min, finallychanged to 95% [water+10 mM NH₄HCO₃] and 5% [CH₃CN] in 0.1 min and underthis condition for 5 min; Purity is 94.4%, Rt=9.055 min.

¹H NMR (400 MHz, DMSO-d₆) δ 0.68-0.73 (3H, m), 0.81-0.84 (3H, m),0.95-0.98 (4H, m), 1.34-1.38 (3H, m), 1.51-1.53 (2H, m), 1.64-1.67 (2H,m), 1.75-1.79 (1H, m), 2.10 (3H, s), 2.20 (3H, s), 2.24 (3H, s), 2.45(3H, s), 3.08-3.11 (2H, m), 3.22-3.27 (3H, m), 3.65-3.73 (2H, m),3.80-3.83 (5H, m), 4.23-4.25 (2H, m), 4.28-4.29 (2H, m), 4.33-4.38 (2H,m), 4.44-4.50 (2H, m), 4.56 (2H, s), 4.67-4.70 (1H, m), 4.90-4.94 (1H,m), 5.08-5.09 (1H, m), 5.85 (1H, s), 7.20-7.22 (3H, m), 7.35-7.37 (2H,m), 7.40-7.46 (5H, m), 7.51-7.53 (2H, m), 7.60-7.62 (2H, m), 8.22 (1H,t, J=4.8 Hz), 8.43 (1H, d, J=7.2 Hz), 8.99 (1H, s), 11.4 (1H, d, J=4.8Hz).

Chemical Formula: C₆₂H₇₃N₇O₉S, Molecular Weight: 1092.35.

Total H count from HNMR data: 73.

Example Synthesis of Exemplary Compound 51 Step 1.2-hydroxy-4-(4-methylthiazol-5-yl)benzonitrile

Into a 500-ml-3-necked round -bottom flash with an inert atmosphere ofnitrogen, 4-bromo-2-hydroxybenzonitrile (26 g, 131.3 mmol, 1.00 equiv),DMA (300 ml), 4-methylthiazole (26, 262.6 mmol, 2.00 equiv), KOAc (26 g,262.6 mmol, 2.00 equiv), Pd(OAc)₂ (884.3 mg, 3.94 mmol, 0.03 equiv). Theresulting solution was stirred for 5 hour at 150° C. The reaction wasthen quenched by the addition of 1000 mL of water. The resulting mixturewas washed with 3×500 mL of ethyl acetate and the organic layerscombined, and the organic layers was washed with 3×500 mL of H₂O. Themixture was dried over anhydrous sodium sulfate and concentrated undervacuum. The residue was applied onto a silica gel column with ethylacetate/petroleum ether (1:1). This resulted in 14.4 g (66.66 mmol,50.77%) of 2-hydroxy-4-(4-methylthiazol-5-yl) benzonitrile as a yellowsolid.

¹HNMR (400 MHz, DMSO-d6): δ 2.49 (s, 3H), 7.08 (d, J=8.0 Hz, 1H), 7.13(s, 1H), 7.71 (d, J=8.0 Hz, 1H), 9.07 (s, 1H), 11.35 (s, 1H).

Step 2. 2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenol

Into a 1000-ml-3-necked round-bottom flash purged and maintained with aninert atmosphere of nitrogen, was placed a solution of2-hydroxy-4-(4-methylthiazol-5-yl) benzonitrile (14.4 g, 66.66 mmol) inTHF 400 ml. This was followed by the addition of LiAlH₄ (6.34 g, 166.67mmol, 2.50 equiv) in several batches at 0° C. The resulting mixture wasfiltered and the filter cake was washed with 10% MeOH in DCM for fourtimes. The combined filtrates were concentrated to afford the crude2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenol 10.4 g (47.27 mmol, 71%yield). It was used to next step without further purification.

¹HNMR (400 MHz, DMSO-d6): δ 2.40 (s, 3H), 3.62 (br, 1H), 6.33 (d, J=6.0Hz, 1H), 6.56 (s, 1H), 6.96 (d, J=7.6 Hz, 1H), 8.82 (s, 1H).

Step 3. (S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoic acid

(S)-2-amino-3-methylbutanoic acid (43.7 g, 373 mmol) was added to asolution of phthalaldehyde (50 g, 373 mmol) in acetonitrile (1000 mL).The resulting mixture was refluxed for overnight. The reaction mixturewas cooled to room temperature then filtered and dried to afford(S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoic acid (72 g, 83%).

Step 4, methyl(2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxylate

A solution of (S)-3-methyl-2-(1-oxoisoindolin-2-yl) butanoic acid (5 g,21.44 mmol), (2S,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate, HCl(4.67 g, 25.7 mmol) DIPEA (8.98 ml, 51.4 mmol) in DMF (Volume: 30 ml)was added HATU (9.78 g, 25.7 mmol) at 0° C., The resulting mixture wasstirred at room temperature for 2 hours. The mixture was partitionedbetween EtOAc and water. The organic phase was washed with water, brineand dried over anhydrous Na₂SO₄. The residue was purified with columnchromatography to afford methyl(2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxylate(5.41 g, 70%).

¹HNMR (400 MHz, CDCl₃): δ 0.84 (d, J=5.6 Hz, 3H), 1.09 (d, J=5.2 Hz,3H), 2.00 (m, 1H), 2.31-2.41 (m, 2H), 3.76 (s, 3H), 3.84 (d, J=11.2 Hz,1H), 4.30-4.38 (m, 2H), 4.56-4.71 (m, 3H), 4.78 (m, 1H), 7.27-7.42 (m,3H), 7.69 (d, J=7.2 Hz, 1H).

Step 5.(2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxylicacid

A solution of (2S,4R)-methyl4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl) butanoyl)pyrrolidine-2-carboxylate (5 g, 13.87 mmol) in Water (Volume: 50 ml),THF (Volume: 100 ml), was added lithium hydroxide, H₂O (1.164 g, 27.7mmol), at 0° C. The reaction was stirred at room temperature for 2hours. The reaction mixture was acidified with 1N HCl to pH 1-2, andextracted with EtOAc. The combined organic layer was washed with brine,dried over Na₂SO₄ and concentrated to afford(2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxylicacid (4.42 g, 92%).

¹HNMR (400 MHz, CDCl₃): δ 0.87 (d, J=6.4 Hz, 3H), 1.05 (d, J=5.6 Hz,3H), 2.21 (m, 1H), 2.31 (m, 1H), 2.43 (m, 1H), 3.80 (d, J=6.4 Hz, 1H),4.37-4.44 (m, 2H), 4.55 (s, 1H), 4.64 (t, J=8.0 Hz, 7.6 Hz, 1H), 4.73(d, J=17.6 Hz, 1H), 4.83 (d, J=10.8 Hz, 1H), 7.38-7.42 (m, 2H), 7.49 (d,J=7.2 Hz, 1H), 7.74 (d, J=7.6 Hz, 1H).

Step 6.(2S,4R)-4-hydroxy-N-(2-hydroxy-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxamide

To a solution of(2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxylicacid (6.00 g, 27.27 mmol, 1.10 equiv),2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenol (8.58 g, 24.79 mmol, 1.00equiv), EDCI (5.70 g, 29.75 mmol, 1.20 equiv), HOBT (4.02 g, 29.75 mmol,1.20 equiv) in CH₂Cl₂ (100 mL), was added Et₃N (6.0 g, 10.75 mmol). Theresulting solution was stirred at room temperature for 1 hour. Themixture was partitioned between CH₂Cl₂ and water. The organic phase waswashed with water, brine and dried over anhydrous Na₂SO₄. The residuewas purified with column chromatography to give(2S,4R)-4-hydroxy-N-(2-hydroxy-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxamide(6.3 g, 11.49 mmol, 46.3% yield)

¹HNMR (400 MHz, CDCl₃): δ 0.81 (d, J=6.4 Hz, 3H), 0.86 (d, J=6.8 Hz,3H), 1.96-2.01 (m, 1H), 2.34-2.40 (m, 1H), 2.44-2.53 (m, 4H), 3.63 (dd,J=3.6, 12.0 Hz 1H), 4.27-4.2 (m, 1H), 4.38-4.43 (m, 2H), 4.53 (s, 2H),4.68-4.71 (m, 3H), 6.91 (d, J=8.0 Hz, 1H), 7.01 (s, 1H), 7.13 (d, J=7.6Hz, 1H), 7.42-7.44 (m, 2H), 7.52 (d, J=7.2 Hz, 1H), 7.78 (d, J=7.2 Hz,1H), 8.01 (s, 1H), 8.66 (s, 1H), 9.20 (br, H). LC-MS (ESI): calcd.548.21; Found, 549.3 (M+H).

Step 7. 4-(Benzyloxy)butan-1-ol

To a solution of 5-(benzyloxy)pentan-1-ol (50 g, 0.56 mol) in DMF (400ml) was added NaH (17.7 g, 0.44 mol) in batches at 0° C. After stirringfor 30 minutes, BnBr (66 g, 0.39 mol) was added dropwise at 0° C. Theresulting suspension was stirred at 20° C. for 30 minutes. Then it washeated to 50° C. for another 2 hours. The reaction was quenched withwater (500 mL) and extracted with of EA (1 L). The organic phase waswashed with brine. The combined organic layers were dried over anhydrousNa₂SO₄. The solvent was removed under vacuum to afford crude desiredproduct 4-(benzyloxy)butan-1-ol (60 g crude, 100% yield), which was usedin next step directly.

¹H NMR: (400 MHz, DMSO): δ 7.28-7.35 (m, 5H), 4.46 (s, 2H), 4.21 (t,J=6.8 Hz, 2H), 3.46 (t, J=6.8 Hz, 2H), 3.15 (s, 3H), 1.61-1.76 (m, 4H).

Chemical Formula: C₁₁H₁₆O₂; Molecular Weight: 180.24

Total H count from ¹HNMR data: 18

Step 8. 3-(4-(Benzyloxy)butoxy)propan-1-ol

To a solution of 4-(benzyloxy)butan-1-ol (12 g, 66.6 mmol) and TEA (20g, 199.9 mmol) in DCM (120 mL) was added MsCl (11.5 g, 100 mmol)dropwise at 0° C. The resulting solution was stirred at 20° C. for 30minutes. The reaction was quenched with water and was washed with brine.The organic phase was dried over anhydrous sodium sulfate. The solventwas removed under vacuum to afford crude desired product (15 g crude),which was used in next step directly.

To a solution of above crude desired product (15 g, 58.1 mmol) in THF(150 ml) were added propane-1,3-diol (11 g, 145 mmol) and NaH (3.72 g,93 mmol) at 0° C. The resulting solution was heated to 80° C. for 16hours. The reaction was quenched with water and extracted with EA (200mL). The organic phase was washed with brine. The combined organiclayers were dried over anhydrous sodium sulfate and concentrated toafford crude desired product 3-(4-(Benzyloxy)butoxy)propan-1-ol (17 gcrude, 100% yield in two steps), which was used in next step directly.

¹H NMR: (400 MHz, DMSO): δ 7.27-7.36 (m, 5H), 4.44 (s, 2H), 4.23 (t,J=6.4 Hz, 2H), 3.38 (m, 7H), 3.15 (s, 3H), 1.89 (m, 2H), 1.56 (m, 4H).

Chemical Formula: C₁₄H₂₂O₃; Molecular Weight: 238.32.

Total H count from ¹HNMR data: 25.

Step 9.2-(4-(3-(4-(Benzyloxy)butoxy)propoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

To a solution of 3-(4-(Benzyloxy)butoxy)propan-1-ol (1 g, 4.2 mmol) andTEA (848 mg, 8.4 mmol) in DCM (20 mL) was added MsCl (722 mg, 6.3 mmol)dropwise at 0° C. The resulting solution was stirred at 20° C. for 30minutes. The reaction was quenched with water and washed with brine. Theorganic layer was dried over anhydrous sodium sulfate. The solvent wasremoved under vacuum to afford crude desired product (1.2 g crude),which was used in next step directly. To a solution of above crudedesired product (600 mg, 1.90 mmol) in dry DMF (6 ml) were added Cs₂CO₃(1.24 g, 3.79 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (420 mg, 1.90 mmol) subsequently. Theresulting solution was heated to 80° C. for 2 hours. The reaction wasdiluted with EA (30 mL) and washed with brine. The organic phase wasdried over anhydrous sodium sulfate and concentrated under vacuum. Theresidue was purified with a column to afford2-(4-(3-(4-(Benzyloxy)butoxy)propoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(EA:PE=1:10) (500 mg, 54% yield in two steps).

¹H NMR: (400 MHz, CDCl₃): δ 7.73 (d, J=8.4 Hz, 2H), 7.32 (m, 5H), 6.88(d, J=8.8 Hz, 2H), 4.49 (s, 2H), 4.08 (t, J=6.4 Hz, 2H), 3.57 (t, J=6.0Hz, 2H), 3.47 (m, 4H), 2.03 (m, 2H), 1.67 (m, 4H), 1.33 (s, 12H).

Chemical Formula: C₂₆H₃₇BO₅; Molecular Weight: 440.38.

Total H count from ¹HNMR data: 37.

Step 10.4-(3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propoxy)butan-1-ol

To a solution of2-(4-(3-(4-(Benzyloxy)butoxy)propoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(500 mg, 1.14 mmol) in MeOH (30 mL) was added Pd(OH)₂/C (250 mg). Theresulting mixture was stirred at 20° C. for 2 hours under H₂ at 1 atm.The mixture was filtered through a Celite pad, and the filtrate wasconcentrated to afford4-(3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propoxy)butan-1-ol(340 mg, 85% yield), which was used in next step directly.

Step 11.(2S,4R)-4-Hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)-2-(4-(3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propoxy)butoxy)benzyl)pyrrolidine-2-carboxamide

To a solution of4-(3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propoxy)butan-1-ol(170 mg, 0.51 mmol) and TEA (155 mg, 1.53 mmol) in DCM (10 mL) was addedMsCl (117 mg, 1.02 mmol) dropwise at 0° C. The resulting solution wasstirred at 20° C. for 30 minutes. The reaction was quenched with waterand washed with brine. The organic layer was dried over anhydrous sodiumsulfate. The solvent was removed under vacuum to afford crude desiredproduct (260 mg crude, 100% yield), which was used in next stepdirectly.

To a solution of above crude desired product (260 mg, 0.61 mmol) in dryDMF (4 ml), was added K₂CO₃ (168 mg, 1.21 mmol) and(2S,4R)-4-hydroxy-N-(2-hydroxy-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxamide(332 mg, 0.61 mmol) subsequently. The resulting solution was stirred at70° C. overnight. The reaction was diluted EA with (30 mL) and washedwith brine. The organic phase was dried over anhydrous sodium sulfateand concentrated under vacuum. The residue was purified by TLC to afford(2S,4R)-4-Hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)-2-(4-(3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propoxy)butoxy)benzyl)pyrrolidine-2-carboxamide(DCM:MeOH=20:1) (90 mg, yield=21%).

¹HNMR: (400 MHz, DMSO): δ 8.98 (s, 1H), 8.35 (m, 1H), 7.71 (d, J=7.2 Hz,2H), 7.58 (m, 4H), 7.48 (m, 1H), 7.32 (d, J=7.2 Hz, 1H), 7.00 (m, 2H),6.91 (d, J=8.4 Hz, 2H), 5.07 (d, J=4.0 Hz, 1H), 4.71 (m, 1H), 4.15-4.60(m, 6H), 4.05 (m, 8H), 3.60-3.80 (m, 2H), 3.40-3.55 (m, 4H), 2.46 (s,3H), 2.35 (m, 1H), 1.65-2.10 (m, 9H), 1.26 (s, 12H), 1.07 (s, 2H), 0.96(d, J=6.4 Hz, 3H), 0.72 (d, J=6.4 Hz, 3H).

Chemical Formula: C₄₈H₆₁BN₄O₉S; Molecular Weight: 880.90.

Total H count from ¹HNMR data: 69.

Step 12. 5-Bromo-2-methyl-3-nitrobenzoic acid

To stirred solution of 2-methyl-3-nitrobenzoic acid (10 g, 55 mmol) inconc. H₂SO₄ (40 mL), 1,3-dibromo-5,5-dimethyl-2,4-imidazolidinedione (9g, 32 mmol) was added portion wise at room temperature and reaction wasstirred at room temperature for 5 hours. Then the reaction mass waspoured on an ice cold water. Solid was filtered, and the resultingresidue was washed with water and dried under vacuum to afford5-Bromo-2-methyl-3-nitrobenzoic acid (12 g, 84%) as a light yellowsolid.

¹H NMR: (400 MHz, DMSO-d₆): δ 8.28 (d, J=2.0 Hz, 1H), 8.13 (d, J=2.0 Hz,1H), 2.51 (s, 3H).

Chemical Formula: C8H6BrNO4; Molecular Weight: 260.04.

Total H count from ¹HNMR data: 5.

Step 13. Methyl 5-bromo-2-methyl-3-nitrobenzoate

A mixture of 5-bromo-2-methyl-3-nitrobenzoic acid (12 g, 41 mmol) inSOCl₂/MeOH (v:v=1:10) (250 mL) was heated to reflux overnight. Thereaction mixture was cooled and concentrated. The residue was dissolvedin 300 mL of EA. The organic layer was washed sequentially with sat. aq.NaHCO₃ and brine, dried over Na₂SO₄, and concentrated. The residue waspurified by chromatography (silica gel, PE:EA (20:1, v:v)) to affordMethyl 5-bromo-2-methyl-3-nitrobenzoate (11 g, yield: 87%).

¹H NMR: (400 MHz, CDCl₃): δ 8.12 (d, J=2.0 Hz, 1H), 7.97 (d, J=2.0 Hz,1H), 3.95 (s, 3H), 2.57 (s, 3H).

Chemical Formula: C9H8BrNO4; Molecular Weight: 272.96.

Total H count from ¹HNMR data: 8.

Step 14. Methyl 3-amino-5-bromo-2-methylbenzoate

To a stirred solution of methyl 3-bromo-5-nitrobenzoate (11 g, 40 mmol)in ethanol (100 mL), was added NH₄Cl solution (13 g in 50 mL water, 240mmol) followed by Fe powder (20 g, 360 mmol). The resulting reaction wasstirred at 80° C. for 2-3 hours. Then the reaction mixture was filteredand the filtrate was concentrated till dryness to give a solid which wasdissolved in sat. sodium bicarbonate solution. Aqueous layer wasextracted with ethyl acetate (3×100 mL). The combined organic layerswere dried over sodium sulfate and concentrated to afford the desiredcompound methyl 3-amino-5-bromo-2-methylbenzoate (8.1 g, 83%).

¹H NMR: (400 MHz, CDCl₃): δ 7.33 (s, 1H), 6.94 (s, 1H), 3.87 (s, 3H),3.79 (br, 2H), 2.28 (s, 3H).

Chemical Formula: C9H10BrNO2; Molecular Weight: 242.99.

Total H count from ¹HNMR data: 10.

Step 15. Methyl 5-bromo-2-methyl-3-((tetrahydro-2H-pyran-4-yl) amino)benzoate

To a solution of methyl 3-amino-5-bromo-2-methylbenzoate (2 g, 8.2 mmol)in DCM (20 mL), and acetic acid (2.5 g, 40 mol) was addeddihydro-2H-pyran-4(3H)-one (1.2 g, mol 12 mmol) at 25° C. After 2.5 h,NaCNBH₃ was added into the reaction in portions and the mixture wasstirred overnight. The reaction was quenched with a solution of sodiumhydroxide (1.6 g, 40 mmol) in water (50 mL). After stirring for 10minutes at ambient temperature, the organic layer was washed with water(2×50 mL), dried (Na₂SO₄) and concentrated. The crude product waspurified by silica gel chromatography eluting with 5-20% ethyl acetatein petroleum to afford Methyl5-bromo-2-methyl-3-((tetrahydro-2H-pyran-4-yl) amino) benzoate (1.3 g,50%) as a light yellow oil.

¹H NMR: (400 MHz, DMSO-d₆): δ 6.97 (s, 1H), 6.93 (s, 1H), 4.99 (d, J=8.0Hz, 1H), 3.87 (d, d, J=10.80 Hz, 2H), 3.80 (s, 3H), 3.60 (br, 1H), 3.44(t, J=11.6 Hz, 3H), 2.15 (s, 3H), 1.84 (d, J=12.4 Hz, 2H), 1348-1.57 (m,2H).

Chemical Formula: C14H18BrNO3; Molecular Weight: 328.2.

Total H count from ¹HNMR data: 18.

Step 16. Methyl 5-bromo-3-[ethyl(oxan-4-yl)amino]-2-methylbenzoate

To a stirred solution of methyl5-bromo-2-methyl-3-[(oxan-4-yl)amino]benzoate (1 g, 119 mmol) in THF (20mL) was added LiHDMS (1.0 M, 2.0 eq, THF) at 0° C. After 30 minutes, EtI(4.0 eq) was added into the mixture at 0° C. Then reaction mixture wasstirred at room temperature for 3 hours. Saturated NaHCO₃ was added andthe mixture was separated. The aqueous layer was extracted with CH₂Cl₂and the combined organic layers were concentrated in vacuo to affordmethyl 5-bromo-3-[ethyl(oxan-4-yl)amino]-2-methylbenzoate (1.2 g crude)which was used into next step without further purification.

Chemical Formula: C16H22BrNO3; Molecular Weight: 356.25.

Step 17.5-Bromo-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzoic acid

To a stirred solution of5-bromo-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzoate (1.2g, crude) in ethanol (15 mL) was added LiOH (0.3 g, 10 mmol) and theresulting mixture was stirred at 60° C. for 1 hours. Upon the completionof the reaction as determined by TLC, the solvent was removed underreduced pressure and the residue was acidified with 1N HCl until pH-5,and it was concentrated. The crude product was purified by silica gelchromatography eluting with 5-10% (CH₃OH/DCM) to afford5-Bromo-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzoic acid(0.7 g, 70%) as a light yellow oil.

¹H NMR: (400 MHz, CDCl₃): δ 7.88 (s, 1H), 7.42 (s, 1H), 3.98 (d, J=11.2Hz, 2H), 3.34 (t, J=11.2 Hz, 2H), 3.03-3.09 (m, 2H), 2.95-3.00 (m, 1H),2.52 (s, 3H), 1.64-1.73 (m, 4H), 0.88 (t, J=6.8 Hz, 3H).

Chemical Formula: C15H20BrNO3; Molecular Weight: 342.23.

Total H count from ¹HNMR data: 19.

Step 18.5-Bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamide

5-Bromo-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzoic acid(0.5 g, 1.5 mmol) was dissolved in DMF (5 mL), and 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one (0.45 g, 2.9 mmol) and DIEA (0.84g, 5.8 mmol) were added. The reaction mixture was stirred at roomtemperature for 15 minutes, and then PYBOP (1.6 g, 3.0 mmol) was added.The mixture was stirred at room temperature for 3 hours. Upon thecompletion of the reaction as determined by TLC, the reaction mixturewas poured onto an ice-cold water (150 mL). The mixture was stirred foranother 10 minutes and the solid was collected by filtration. The solidwas washed with water (50 mL) and dried by air. Then the solid wasslurried in 5% MeOH in DCM solution to afford desired product5-Bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamideas a solid (200 mg, 30%).

¹H NMR: (DMSO-d₆, 400 MHz) δ 11.46 (s, 1H), 8.21 (s, 1H), 7.31 (s, 1H),7.09 (s, 1H), 5.86 (s, 1H), 4.26 (d, J=4.4 Hz, 2H), 3.83 (d, J=9.60 Hz,2H), 3.20-3.27 (m, 2H), 3.00-3.02 (m, 3H), 2.19 (s, 3H), 2.15 (s, 3H),2.11 (s, 3H), 1.48-1.62 (m, 4H), 0.78 (t, J=6.8 Hz, 3H).

Chemical Formula: C23H30BrN3O3; Molecular Weight: 476.41.

Total H count from ¹HNMR data: 30.

Step 19.(2S,4R)—N-(2-(4-(3-((3′-(((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-5′-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4′-methyl-[1,1′-biphenyl]-4-yl)oxy)propoxy)butoxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxamide

To a solution of5-Bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamide(43 mg, 0.091 mmol) and(2S,4R)-4-Hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)-2-(4-(3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propoxy)butoxy)benzyl)pyrrolidine-2-carboxamide(80 mg, 0.091 mmol) in dioxane (5 mL)/H₂O (0.5 mL) were added Cs₂CO₃ (74mg, 0.227 mmol), Pd(dppf)C₁₂ (26 mg, 0.036 mmol) andtri-tert-butylphosphine tetrafluoroborate (21 mg, 0.073 mmol)subsequently. After stirring at 100° C. for 2 hours under nitrogenatmosphere, the reaction mixture was diluted with ethyl acetate (30 mL),and the organic layer was washed with brine (20 mL×3). The organic phasewas dried over anhydrous sodium sulfate and concentrated under vacuum.The residue was purified by prep-TLC (DCM/MeOH 19/1) first and then byprep-HPLC to afford the desired product(2S,4R)—N-(2-(4-(3-((3′-(((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-5′-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4′-methyl-[1,1′-biphenyl]-4-yl)oxy)propoxy)butoxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxamide(34 mg, 32% yield).

¹H NMR: (400 MHz, MeOD): δ 8.74 (s, 1H), 7.67 (d, J=8.0 Hz, 1H),7.28-7.55 (m, 7H), 7.15 (s, 1H), 6.82 (m, 4H), 5.98 (s, 1H), 4.30-4.53(m, 10H), 3.97 (t, J=6.4 Hz, 4H), 3.80 (m, 4H), 3.54 (t, J=6.0 Hz, 2H),3.47 (t, J=6.0 Hz, 2H), 3.25 (m, 1H), 3.04 (m, 6H), 2.36 (s, 3H), 2.28(s, 3H), 2.21 (s, 3H), 2.12 (s, 3H), 1.45-2.10 (m, 16H), 0.92 (d, J=6.4Hz, 3H), 0.78 (t, J=7.2 Hz, 3H), 0.70 (d, J=6.8 Hz, 3H).

Chemical Formula: C₆₅H₇₉N₇O₁₀S; Molecular Weight: 1150.43.

Total H count from ¹HNMR data: 81.

LC-MS: (ES⁺): m/z 575.9 [M+H]⁺, t_(R)=4.00 min.

Example Synthesis of Exemplary Compound 43 Step 1. Tert-butyl2-(2-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-ylphenoxy)ethoxy)ethoxy)acetate

To a solution of tert-butyl 2-(2-(2-hydroxyethoxy)ethoxy)acetate (1.0 g,4.54 mmol) and Et₃N (1.37 g, 13.6 mmol) in DCM (15 mL) were added MsCl(779.7 mg, 6.81 mmol) dropwise at 0° C. The resulting solution wasstirred at 30° C. for 1 hour. The solvent was evaporated under reducedpressure. The residue was diluted with EA (30 mL), washed with brinetwice. The organic phase was dried over Na₂SO₄, concentrated underreduced pressure. The residue was used for next step without furtherpurification.

A solution of the above intermediate and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol in DMF (10 mL) wasadded Cs₂CO₃(2.62 g, 8.04 mmol). The resulting mixture was stirred at70° C. for 1 hour. After cooling to room temperature, the reaction wasdiluted with EA (30 mL), washed with brine twice. The organic phase wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography on silica gel (PE/EA=8/1) to afford tert-butyl2-(2-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethoxy)ethoxy)acetate(1.6 g, 78.5% yield) as a colorless oil.

Step 2. Tert-butyl2-(2-(2-((3′-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-5′-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4′-methyl-[1,1′-biphenyl]-4-yl)oxy)ethoxy)ethoxy)acetate

To a solution of tert-butyl2-(2-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethoxy)ethoxy)acetate(400 mg, 0.92 mmol) and5-bromo-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methyl-N-((4-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzamide(432 mg, 0.92 mmol) in dioxane/H₂O (10 mL, 10:1) were addedt-Bu₃PHBF₄(106.3 mg, 0.37 mmol), CsF (557.4 mg, 3.67 mmol), Cy2NMe (5drops) and Pd₂(dba)₃ (167.9 mg, 0.18 mmol) subsequently. The resultingmixture was stirred at 100° C. for 2 hours under N₂ 1 atm. After coolingto room temperature, the reaction was diluted with EA (30 mL), and themixture was washed with brine twice. The organic phase was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography on silica gel (DCM/MeOH=40/1) to affordtert-butyl-2-(2-(2-((3′-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-5′-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4′-methyl-[1,1′-biphenyl]-4-yl)oxy)ethoxy)ethoxy)acetate(520 mg, 82.0% yield) as a colorless oil.

LC-MS: (ES⁺): m/z 693.3 [M+H]⁺, t_(R)=3.78 min.

Step 3.2-(2-(2-((3′-(((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-5′-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4′-methyl-[1,1′-biphenyl]-4-yl)oxy)ethoxy)ethoxy)aceticacid

To a solution of tert-butyl2-(2-(2-((3′-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-5′-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4′-methyl-[1,1′-biphenyl]-4-yl)oxy)ethoxy)ethoxy)acetate(520 mg, 0.75 mmol) in dioxane (10 mL) were HCl(g)/dioxane (6 N, 5 mL).The resulting mixture was stirred at 25° C. for 3 hours. The solvent wasremoved under vacuum to afford2-(2-(2-((3′-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-5′-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4′-methyl-[1,1′-biphenyl]-4-yl)oxy)ethoxy)ethoxy)aceticacid (400 mg. 83.6% yield) as a yellow solid.

LC-MS: (ES⁺): m/z 636.3 [M+H]⁺, t_(R)=3.13 min.

Step 4.2-(2-(2-((3′-(((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-5′-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4′-methyl-[1,1′-biphenyl]-4-yl)oxy)ethoxy)ethoxy)aceticacid

To a solution of2-(2-(2-((3′-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-5′-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4′-methyl-[11,1′-biphenyl]-4-yl)oxy)ethoxy)ethoxy)aceticacid (400 mg, 0.60 mmol) in DMF (10 mL) were added(2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N—((S)-1-(4-(4-methyl-thiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamidehydrochloride (572.2 mg, 1.19 mmol), PyBOP (620.2 mg, 1.19 mmol) andDIPEA (307.4 mg, 2.38 mmol) subsequently. The resulting mixture wasstirred at 25° C. for 1.5 hours. The mixture was diluted with EA (30mL), washed with brine twice. The organic phase was evaporated underreduced pressure. The residue was purified by prep-HPLC to afford(2S,4R)-1-((S)-2-(2-(2-(2-((3′-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-5′-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4′-methyl-[1,1′-biphenyl]-4-yl)oxy)ethoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N—((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide(100 mg, 15.8% yield) as a white solid.

¹HNMR: (400 MHz, CDCl₃) δ 10.53 (br, 2H), 8.67 (s, 1H), 7.41-7.54 (m,4H), 7.35 (dd, J=17.5, 8.2 Hz, 4H), 7.28 (s, 1H), 7.20 (s, 1H), 6.99 (d,J=8.5 Hz, 2H), 5.90 (s, 1H), 5.01-5.12 (m, 1H), 4.75 (t, J=7.6 Hz, 1H),4.70 (d, J=8.9 Hz, 1H), 4.62 (dd, J=14.1, 6.4 Hz, 1H), 4.51 (s, 1H),4.39 (dd, J=14.3, 5.4 Hz, 1H), 4.31 (s, 1H), 4.19 (d, J=11.1 Hz, 3H),4.10-3.98 (m, 2H), 3.97-3.83 (m, 5H), 3.75 (d, J=4.2 Hz, 2H), 3.65-3.72(m, 2H), 3.58 (d, J=8.6 Hz, 1H), 3.31 (s, 2H), 3.08 (d, J=6.8 Hz, 2H),3.00 (s, 1H), 2.51 (m, 4H), 2.43 (s, 3H), 2.36 (s, 3H), 2.19 (s, 3H),1.95-2.05 (m, 1H), 1.72 (m, 2H), 1.44 (d, J=6.9 Hz, 3H), 1.07 (s, 9H),0.87 (t, J=6.9 Hz, 3H).

Chemical Formula: C₅₈H₇₅N₇O₁₀S; Molecular Weight: 1062.32.

Total H count from ¹HNMR data: 75.

LC-MS: (ES⁺): m/z 1062.5 [M+H]⁺, t_(R)=3.53 min.

Protein Level Control

This description also provides methods for the control of protein levelswith a cell. This is based on the use of compounds as described herein,which are known to interact with a specific target protein such thatdegradation of a target protein in vivo will result in the control ofthe amount of protein in a biological system, preferably to a particulartherapeutic benefit.

The following examples are used to assist in describing the presentdisclosure, but should not be seen as limiting the present disclosure inany way.

Assays and Degradation Data

Protocol of the Cellular Assay of Target Protein Degradation (VCaPCells, ELISA).

For detection Cell Signaling PathScan Sandwich ELISA Catalog #12850 Lot11 was used. VCaP cells were cultured in ATCC DMEM+ATCC FBS and plated40,000/well 100 μl/well in RPMI P/S with 5% CSS Omega (bovine) seruminto a 96 well plate. The cells were grown for a minimum of 3 days,dosed with compounds in 0.1% DMSO (diluted with 5% CSS) and incubatedwith aspiration for 4 hours. 100 μl of 1× Cell Signaling lysis buffer#9803 (36 mL dH₂O+4 mL Cell Signaling lysis buffer) was added. Theincubation was placed on cold room shaker for 10 minutes at speed 8-9. 5μl to 100 μL of Diluent was transferred to ELISA plate (0.15 μg/mL−0.075μg/mL) and stored at 4° C. overnight on cold room shaker speed 5 (gentleswirl) and then shaken next morning at 37° C. for 30 minutes. Thepreparation was washed 4×200 μl with ELISA wash buffer and aspiratedwith eight-channel aspirator. 100 μl/well of target protein detectionantibody was added after, which the preparation was covered and shakenat 37° C. for 1 hour. 100 μl TMB was added, and the mixture was shakenfor 5 min while under observation. When TMB turned light blue, 100 μl ofStop solution was added, and the mixture was shaken and read at 450 nM.Also read at 562 nm for background subtraction.

Exemplary compounds (or compounds) are shown in Table 1 below with theassociated degradation data shown in Table 2 below.

TABLE 1 Exemplary compounds of the present disclosure Mass Spec (M + H)⁺unless Ex # Structure otherwise noted Name 1

1-cyclopentyl-N-[(4,6- dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-6- [4-({4-[2-({[(2S)-1-[(2S,4R)-4-hydroxy-2-({[4-(4-methyl-1,3- thiazol-5- yl)phenyl]methyl}carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1- oxobutan-2- yl]carbamoyl}methoxy)ethyl]piperazin-1-yl}methyl)phenyl]- 1H-indole-4-carboxamide 2

1096.55 1-cyclopentyl-N-[(4,6- dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-6- {4-[(4-{2-[2-({[(2S)-1-[(2S,4R)-4-hydroxy-2-({[4-(4- methyl-1,3-thiazol-5-yl)phenyl]methyl}carbamoyl) pyrrolidin-1-yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl}methoxy)ethoxy] ethyl)piperazin-1-yl)methyl]phenyl}-1H-indole- 4-carboxamide 3

1124.58 1-cyclopentyl-N-[(4,6- dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-6- {4-[(4-{2-[4-({[(2S)-1-[(2S,4R)-4-hydroxy-2-({[4-(4- methyl-1,3-thiazol-5-yl)phenyl]methyl}carbamoyl) pyrrolidin-1-yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl}methoxy)butoxy] ethyl}piperazin-1-yl)methyl]phenyl}-1H-indole- 4-carboxamide 4

1169.61 1-cyclopentyl-N-[(4,6- dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-6- (4-{[4-(2-{3-[3-({[(2S)-1-[(2S,4R)-4-hydroxy-2-({[4(4- methyl-1,3-thiazol-5-yl)phenyl]methyl}carbamoyl) pyrrolidin-1-yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl}methoxy)propoxy] propoxy}ethyl)piperazin-1-yl]methyl}phenyl)-1H-indole- 4-carboxamide 5

1196.65 1-cyclopentyl-N-[(4,6- dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-6- (4-{[4-(2-{4-[4-({[(2S)-1-[(2S,4R)-4-hydroxy-2-({[4-(4- methyl-1,3-thiazol-5-yl)phenyl]methyl}carbamoyl) pyrrolidin-1-yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl}methoxy)butoxy] butoxy}ethyl)piperazin-1-yl]methyl}phenyl)-1H-indole- 4-carboxamide 6

1224.68 1-cyclopentyl-N-[(4,6- dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-6- [4-[(4-{2-[(5-{[5-({[(2S)-1-[(2S,4R)-4-hydroxy-2-({[4-(4- methyl-1,3-thiazol-5-yl)phenyl]methyl}carbamoyl) pyrrolidin-1-yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl}methoxy)pentyl] oxy}pentyl)oxy]ethyl}piperazin-1-yl)methyl]phenyl}-1H- indole-4-carboxamide 7

(M + Na)⁺ = 888.4 N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-1- [1-(1-{1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo- 2,3-dihydro-1H-isoindol-4-yl]-4,7,10-trioxa-1- azadodecanoyl}piperidin-4-yl)ethyl]-2-methyl-1H-indole- 3-carboxamide 8

1081.5 N-[(4,6-dimethyl-2-oxo-1,2- dihydropyridin-3-yl)methyl]-1-{1-[1-(1-{[(2S)-1-[(2S,4R)-4- hydroxy-2-({[4-(4-methyl-1,3- thiazol-5-yl)phenyl]methyl}carbamoyl) pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamoyl}- 2,5,8,11- tetraoxatridecanoyl)piperidin-4-yl]ethyl}-2-methyl-1H-indole- 3-carboxamide 9

1037.4 N-[(4,6-dimethyl-2-oxo-1,2- dihydropyridin-3-yl)methyl]-1-{1-[1-(2-{2-[2-({[(2S)-1- [(2S,4R)-4-hydroxy-2-({[4-(4-methyl-1,3-thiazol-5- yl)phenyl]methyl}carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl}methoxy)ethoxy] ethoxy}acetyl)piperidin-4-yl]ethyl}-2-methyl-1H-indole- 3-carboxamide 10

(M + 2H)⁺/ 2 = 455.8 N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-1- [1-(1-{1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo- 2,3-dihydro-1H-isoindol-4-yl]-4,7,10,13-tetraoxa-1- azapentadecanoyl}piperidin-4-yl)ethyl]-2-methyl-1H-indole- 3-carboxamide 11

(M + 2H)⁺/ 2 = 563.3 N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-1- {1-[1-(1-{[(2S)-1-[(2S,4R)-4-hydroxy-2-({[4-(4-methyl-1,3- thiazol-5- yl)phenyl]methyl}carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1- oxobutan-2-yl]carbamoyl}- 2,5,8,11,14-pentaoxahexadecanoyl)piperidin- 4-yl]ethyl}-2-methyl-1H-indole-3-carboxamide 12

954.4 N-[(4,6-dimethyl-2-oxo-1,2- dihydropyridin-3-yl)methyl]-1-[1-(1-{1-[2-(2,6- dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]- 4,7,10,13,16-pentaoxa-1-azaoctadecanoyl}piperidin-4- yl)ethyl]-2-methyl-1H-indole- 3-carboxamide13

1092.6 (2S,4R)-1-[(2S)-2-{1-[4-(3- {[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3- yl)methyl]carbamoyl}-5- [ethyl(oxan-4-yl)amino]-4-methylphenyl)phenyl]-1,4,7,10- tetraoxadodecan-12-amido}-3,3-dimethylbutanoyl]-4- hydroxy-N-{[4-(4-methyl-1,3- thiazol-5-yl)phenyl]methyl}pyrrolidine- 2-carboxamide 14

1136.7 (2S,4R)-1-[(2S)-2-{1-[4-(3- {[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3- yl)methyl]carbamoyl}-5- [ethyl(oxan-4-yl)amino]-4-methylphenyl)phenyl]- 1,4,7,10,13- pentaoxapentadecan-15-amido}-3,3-dimethylbutanoyl]- 4-hydroxy-N-{[4-(4-methyl- 1,3-thiazol-5-yl)phenyl]methyl}pyrrolidine- 2-carboxamide 15

1180.8 (2S,4R)-1-[(2S)-2-{1-[4-(3- {[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3- yl)methyl]carbamoyl}-5- [ethyl(oxan-4-yl)amino]-4-methylphenyl)phenyl]- 1,4,7,10,13,16- hexaoxaoctadecan-18-amido}-3,3-dimethylbutanoyl]-4- hydroxy-N-{[4-(4-methyl-1,3- thiazol-5-yl)phenyl]methyl}pyrrolidine- 2-carboxamide 16

1224.8 (2S,4R)-1-[(2S)-2-{1-[4-(3- {[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3- yl)methyl]carbamoyl}-5- [ethyl(oxan-4-yl)amino]-4-methylphenyl)phenyl]- 1,4,7,10,13,16,19- heptaoxahenicosan-21-amido}-3,3-dimethylbutanoyl]-4- hydroxy-N-{[4-(4-methyl-1,3- thiazol-5-yl)phenyl]methyl}pyrrolidine- 2-carboxamide 17

921.5 N-[(4,6-dimethyl-2-oxo-1,2- dihydropyridin-3-yl)methyl]-5-[4-({1-[2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-4,7,10-trioxa- 1-azadodecan-12-yl}oxy)phenyl]-3-[ethyl(oxan- 4-yl)amino]-2- methylbenzamide 18

965.6 N-[(4,6-dimethyl-2-oxo-1,2- dihydropyridin-3-yl)methyl]-5-[4-({1-[2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-4,7,10,13- tetraoxa-1-azapentadecan-15-yl}oxy)phenyl]-3-[ethyl(oxan- 4-yl)amino]-2- methylbenzamide 19

1009.3 N-[(4,6-dimethyl-2-oxo-1,2- dihydropyridin-3-yl)methyl]-5-[4-({1-[2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-4,7,10,13,16- pentaoxa-1-azaoctadecan-18-yl}oxy)phenyl]-3-[ethyl(oxan- 4-yl)amino]-2- methylbenzamide 20

1053.6 N-[(4,6-dimethyl-2-oxo-1,2- dihydropyridin-3-yl)methyl]-5-[4-({1-[2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]- 4,7,10,13,16,19-hexaoxa-1- azahenicosan-21-yl}oxy)phenyl]-3-[ethyl(oxan- 4-yl)amino]-2- methylbenzamide 21

1009.5 N-[(4,6-dimethyl-2-oxo-1,2- dihydropyridin-3-yl)methyl]-5-[3-({1-[2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-4,7,10,13,16- pentaoxa-1-azaoctadecan-18-yl}oxy)phenyl]-3-[ethyl(oxan- 4-yl)amino]-2- methylbenzamide 22

1097.6 N-[(4,6-dimethyl-2-oxo-1,2- dihydropyridin-3-yl)methyl]-5-[4-({1-[2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]- 4,7,10,13,16,19,22-heptaoxa-1- azatetracosan-24-yl}oxy)phenyl]-3-[ethyl(oxan- 4-yl)amino]-2- methylbenzamide 23

(M + 2H)⁺/ 2 = 571.6 N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-5- [4-({l-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro- 1H-isoindol-4-yl]-4,7,10,13,16,19,22,25-octaoxa- 1-azaheptacosan-27-yl}oxy)phenyl]-3-[ethyl(oxan- 4-yl)amino]-2- methylbenzamide 24

(M + 3H)⁺/ 3 = 421.9 (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2- fluorophenyl)-4-cyano-N-[4-({1-[4-(3-{[(4,6-dimethyl-2- oxo-1,2-dibydropyridin-3-yl)methyl]carbamoyl}-5- [ethyl(oxan-4-yl)amino]-4-methylphenyl)phenyl]-1,4,7,10- tetraoxadodecan-12- yl}carbamoyl)-2-methoxyphenyl]-5-(2,2- dimethylpropyl)pyrrolidine-2- carboxamide 25

1009.6 N-[(4,6-dimethyl-2-oxo-1,2- dihydropyridin-3-yl)methyl]-5-[2-({1-[2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-4,7,10,13,16- pentaoxa-1-azaoctadecan-18-yl}oxy)phenyl]-3-[ethyl(oxan- 4-yl)amino]-2- methylbenzamide 26

1074.7 5-[4-(2-{2-[2-(4-{2-[(3aR,7aS)- 1-[(2S)-2-cyclohexyl-2-[(2S)-2-(methylamino)propanamido] acetyl]-octahydro-1H-pyrrolo[2,3- c]pyridin-6-yl]ethyl}phenoxy)ethoxy]ethoxy} ethoxy)phenyl]-N-[(4,6-dimethyl-2-oxo-1,2- dihydropyridin-3-yl)methyl]-3-[ethyl(oxan-4-yl)amino]-2- methylbenzamide 27

1351.7 (2R,3S,4R,5S)-3-(3-chloro-2- fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-N-[4- ({1-[4-(3-{[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3- yl)methyl]carbamoyl}-5-[ethyl(oxan-4-yl)amino]-4- methylphenyl)phenyl- 1,4,7,10,13,16-hexaoxaoctadecan-18- yl}carbamoyl)-2- methoxyphenyl]-5-(2,2-dimethylpropyl)pyrrolidine-2- carboxamide 28

(M + 3H)⁺/ 3 = 375.5 5-{4-[2-(2-{2-[(4-{2-[(2S)-1-[(2S)-2-cyclohexyl-2-[(2S)-2- (methylamino)propanamido]acetyl]pyrrolidin-2-yl]-1,3-thiazol- 4-yl}naphthalen-1-yl)oxy]ethoxy}ethoxy)ethoxy] phenyl}-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3- yl)methyl]-3-[ethyl(oxan-4-yl)amino]-2-methylbenzamide 29

1162.7 5-(4-{[1-(4-{2-[(3aR,7aS)-1- [(2S)-2-cyclohexyl-2-[(2S)-2-(methylamino)propanamido] acetyl]-octahydro-1H-pyrrolo[2,3-c]pyridin-6-yl]ethyl]phenyl)- 1,4,7,10,13- pentaoxapentadecan-15-yl]oxy}phenyl)-N-[(4,6- dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-3- [ethyl(oxan-4-yl)amino]-2-methylbenzamide 30

1212.6 5-(4-{[1-(4-{2-[(2S)-1-[(2S)-2- cyclohexyl-2-[(2S)-2-(methylamino)propanamido] acetyl]pyrrolidin-2-yl]-1,3-thiazol-4-yl}naphthalen-1-yl)- 1,4,7,10,13- pentaoxapentadecan-15-yl]oxy}phenyl)-N-[(4,6- dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-3- [ethyl(oxan-4-yl)amino]-2-methylbenzamide 31

(M + 2H)⁺/ 2 = 525.4 (2S,4R)-1-[(2S)-2-[2-(2-2-[4-(3-{[(4,6-dimethyl-2-oxo-1,2- dihydropyridin-3- yl)methyl]carbamoyl}-5-[ethyl(oxan-4-yl)amino]-4- methylphenyl)phenoxy]ethoxy}ethoxy)acetamido]-3,3- dimethylbutanoyl]-4-hydroxy-N-{[4-(4-methyl-1,3-thiazol-5- yl)phenyl]methyl}pyrrolidine-2-carboxamide 32

(M + 3H)⁺/ 3 = 335.5 (2S,4R)-1-[(2S)-2-(2-{2-[4-(3-{[(4,6-dimethyl-2-oxo-1,2- dihydropyridin-3- yl)methyl]carbamoyl}-5-[ethyl(oxan-4-yl)amino]-4- methylphenyl)phenoxy]ethoxy} acetamido)-3,3-dimethylbutanoyl]-4-hydroxy- N-{[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}pyrrolidine- 2-carboxamide 33

(M + 2H)⁺/ 2 = 439.3 N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-5- (4-{2-[2-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo- 2,3-dihydro-1H-isoindol-4-yl]amino}ethoxy)ethoxy]ethoxy} phenyl)-3-[ethyl(oxan-4-yl)amino]-2-methylbenzamide 34

833.3 N-[(4,6-dimethyl-2-oxo-1,2- dihydropyridin-3-yl)methyl]-5-{4-[2-(2-{[2-(2,6- dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4- yl]amino}ethoxy)ethoxy]phenyl}-3-[ethyl(oxan-4-yl)amino]-2- methylbenzamide 35

(M + 2H)⁺/ 2 = 620.9 (2S,4R)-N-{[2-({1-[4-(3-{[(4,6- dimethyl-2-oxo-1,2-dihydropyridin-3- yl)methyl]carbamoyl}-5- [ethyl(oxan-4-yl)amino]-4-methylphenyl)phenyl]- 1,4,7,10,13- pentaoxapentadecan-15-yl}oxy)-4-(4-methyl-1,3- thiazol-5-yl)phenyl]methyl}-4-hydroxy-1-[(2S)-3-methyl-2-(1- oxo-2,3-dihydro-1H-isoindol-2-yl)butanoyl]pyrrolidine-2- carboxamide 36

1197.4 (2S,4R)-N-{[2-({1-[4-(3-{[(4,6- dimethyl-2-oxo-1,2-dihydropyridin-3- yl)methyl]carbamoyl}-5- [ethyl(oxan-4-yl)amino]-4-methylphenyl)phenyl]-1,4,7,10- tetraoxadodecan-12-yl}oxy)-4-(4-methyl-1,3-thiazol-5- yl)phenyl]methyl}-4-hydroxy-1-[(2S)-3-methyl-2-(1-oxo-2,3- dihydro-1H-isoindol-2-yl)butanoyl]pyrrolidine-2- carboxamide 37

(M + 2H)⁺/ 2 = 576.8 (2S,4R)-N-({2-[2-(2-{2-[4(3-{[(4,6-dimethyl-2-oxo-1,2- dihydropyridin-3- yl)methyl]carbamoyl}-5-[ethyl(oxan-4-yl)amino]-4- methylphenyl)phenoxy]ethoxy}ethoxy)ethoxy]-4-(4-methyl- 1,3-thiazol-5- yl)phenyl}methyl)-4-hydroxy-1-[(2S)-3-methyl-2-(1-oxo-2,3- dihydro-1H-isoindol-2-yl)butanoyl]pyrrolidine-2- carboxamide 38

(M + 2H)⁺/ 2 = 555.0 (2S,4R)-N-{[2-(2-{2-[4-(3-{[(4,6-dimethyl-2-oxo-1,2- dihydropyridin-3- yl)methyl]carbamoyl}-5-[ethyl(oxan-4-yl)amino]-4- methylphenyl)phenoxy]ethoxy}ethoxy)-4-(4-methyl-1,3- thiazol-5-yl)phenyl]methyl}-4-hydroxy-1-[(2S)-3-methyl-2-(1- oxo-2,3-dihydro-1H-isoindol-2-yl)butanoyl]pyrrolidine-2- carboxamide 39

(M + 2H)⁺/ 2 = 576.3 (2S,4R)-N-({2-[3-(3-{3-[4-(3-{[(4,6-dimethyl-2-oxo-1,2- dihydropyridin-3- yl)methyl]carbamoyl}-5-[ethyl(oxan-4-yl)amino]-4- methylphenyl)phenoxy]propoxy}propoxy)propoxy]-4-(4- methyl-1,3-thiazol-5-yl)phenyl}methyl)-4-hydroxy- 1-[(2S)-3-methyl-2-(1-oxo-2,3-dihydro-1H-isoindol-2- yl)butanoyl]pyrrolidine-2- carboxamide 40

(M + 2H)⁺/ 2 = 576.3 (2S,4R)-N-{[2-(3-{4-[4-(3-{[(4,6-dimethyl-2-oxo-1,2- dihydropyridin-3- yl)methyl]carbamoyl}-5-[ethyl(oxan-4-yl)amino]-4- methylphenyl)phenoxy]butoxy}propoxy)-4-(4-methyl-1,3- thiazol-5-yl)phenyl]methyl}-4-hydroxy-1-[(2S)-3-methyl-2-(1- oxo-2,3-dihydro-1H-isoindol-2-yl)butanoyl]pyrrolidine-2- carboxamide 41

(M + 2H)⁺/ 2 = 509.8 (2S,4R)-1-[(2S)-2-(2-{3-[4-(3-{[(4,6-dimethyl-2-oxo-1,2- dihydropyridin-3- yl)methyl]carbamoyl}-5-[ethyl(oxan-4-yl)amino]-4- methylphenyl)phenoxy]propoxy} acetamido)-3,3-dimethylbutanoyl]-4-hydroxy- N-{[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}pyrrolidine- 2-carboxamide 42

(M + 2H)⁺/ 2 = 516.8 (2S,4R)-1-[(2S)-2-(2-{4-[4-(3-{[(4,6-dimethyl-2-oxo-1,2- dihydropyridin-3- yl)methyl]carbamoyl}-5-[ethyl(oxan-4-yl)amino]-4- methylphenyl)phenoxy]butoxy} acetamido)-3,3-dimethylbutanoyl]-4-hydroxy- N-{[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}pyrrolidine- 2-carboxamide 43

1062.5 (2S,4R)-1-[(2S)-2-[2-(2-{2-[4- (3-{[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3- yl)methyl]carbamoyl}-5- [ethyl(oxan-4-yl)amino]-4-methylphenyl)phenoxy]ethoxy} ethoxy)acetamido]-3,3-dimethylbutanoyl]-4-hydroxy- N-[(1S)-1-[4-(4-methyl-1,3- thiazol-5-yl)phenyl]ethyl]pyrrolidine-2- carboxamide 44

(M + 3H)⁺/ 3 = 349.0 (2S,4R)-1-[(2S)-2-(5-{3-[4-(3-{[(4,6-dimethyl-2-oxo-1,2- dihydropyridin-3- yl)methyl]carbamoyl}-5-[ethyl(oxan-4-yl)amino]-4- methylphenyl)phenyl]propoxy}pentanamido)-3,3- dimethylbutanoyl]-4-hydroxy-N-{[4-(4-methyl-1,3-thiazol-5- yl)phenyl]methyl}pyrrolidine-2-carboxamide 45

(M + 2H)⁺/ 2 = 531.8 (2S,4R)-1-[(2S)-2-[2-(2-{3-[4-(3-{[(4,6-dimethyl-2-oxo-1,2- dihydropyridin-3- yl)methyl]carbamoyl}-5-[ethyl(oxan-4-yl)amino]-4- methylphenyl)phenoxy]propoxy}ethoxy)acetamido]-3,3- dimethylbutanoyl]-4-hydroxy-N-{[4-(4-methyl-1,3-thiazol-5- yl)phenyl]methyl}pyrrolidine-2-carboxamide 46

(M + 2H)⁺/ 2 = 523.8 (2S,4R)-1-[(2S)-2-[2-({5-[4-(3-{[(4,6-dimethyl-2-oxo-1,2- dihydropyridin-3- yl)methyl]carbamoyl}-5-[ethyl(oxan-4-yl)amino]-4- methylphenyl)phenoxy]pentyl}oxy)acetamido]-3,3- dimethylbutanoyl]-4-hydroxy-N-{[4-(4-methyl-1,3-thiazol-5- yl)phenyl]methyl}pyrrolidine-2-carboxamide 47

(M + 2H)⁺/ 2 = 523.9 (2S,4R)-1-[(2S)-2-[2-(2-{3-[4-(3-{[(4,6-dimethyl-2-oxo-1,2- dihydropyridin-3- yl)methyl]carbamoyl}-5-[ethyl(oxan-4-yl)amino]-4- methylphenyl)phenyl]propoxy}ethoxy)acetamido]-3,3- dimethylbutanoyl]-4-hydroxy-N-{[4-(4-methyl-1,3-thiazol-5- yl)phenyl]methyl}pyrrolidine-2-carboxamide 48

1076.4 (2S,4R)-1-[(2S)-2-[2-(3-{3-[4- (3-{[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3- yl)methyl]carbamoyl}-5- [ethyl(oxan-4-yl)amino]-4-methylphenyl)phenoxy]propoxy} propoxy)acetamido]-3,3-dimethylbutanoyl]-4-hydroxy- N-{[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}pyrrolidine- 2-carboxamide 49

(M + 2H)⁺/ 2 = 576.0 (2S,4R)-N-({2-[(5-{2-[4-(3-{[(4,6-dimethyl-2-oxo-1,2- dihydropyridin-3- yl)methyl]carbamoyl}-5-[ethyl(oxan-4-yl)amino]-4- methylphenyl)phenoxy]ethoxy}pentyl)oxy]-4-(4-methyl-1,3- thiazol-5-yl)phenyl}methyl)-4-hydroxy-1-[(2S)-3-methyl-2-(1- oxo-2,3-dihydro-1H-isoindol-2-yl)butanoyl]pyrrolidine-2- carboxamide 50

1150.4 (2S,4R)-N-({2-[2-({5-[4-(3- {[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3- yl)methyl]carbamoyl}-5- [ethyl(oxan-4-yl)amino]-4-methylphenyl)phenoxy]pentyl} oxy)ethoxy]-4-(4-methyl-1,3-thiazol-5-yl)phenyl}methyl)-4- hydroxy-1-[(2S)-3-methyl-2-(1-oxo-2,3-dihydro-1H-isoindol-2- yl)butanoyl]pyrrolidine-2- carboxamide 51

(M + 2H)⁺/ 2 = 575.9 (2S,4R)-N-{[2-(4-{3-[4-(3-{[(4,6-dimethyl-2-oxo-1,2- dihy dropy ridin-3- yl)methyl]carbamoyl}-5-[ethyl(oxan-4-yl)amino]-4- methylphenyl)phenoxy]propoxy}butoxy)-4-(4-methyl-1,3- thiazol-5-yl)phenyl]methyl}-4-hydroxy-1-[(2S)-3-methyl-2-(1- oxo-2,3-dihydro-1H-isoindol-2-yl)butanoyl]pyrrolidine-2- carboxamide 52

(M + 2H)⁺/ 2 = 575.8 (2S,4R)-N-{[2-(3-{4-[4-(3-{[(4,6-dimethyl-2-oxo-1,2- dihydropyridin-3- yl)methyl]carbamoyl}-5-[ethyl(oxan-4-yl)amino]-4- methylphenyl)phenoxy]butoxy}propoxy)-4-(4-methyl-1,3- thiazol-5-yl)phenyl]methyl}-4-hydroxy-1-[(2S)-3-methyl-2-(1- oxo-2,3-dihydro-1H-isoindol-2-yl)butanoyl]pyrrolidine-2- carboxamide 53

1136.4 (2S,4R)-N-{[2-(2-{4-[4-(3- {[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3- yl)methyl]carbamoyl}-5- [ethyl(oxan-4-yl)amino]-4-methylphenyl)phenoxy]butoxy} ethoxy)-4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}-4- hydroxy-1-[(2S)-3-methyl-2-(1-oxo-2,3-dihydro-1H-isoindol-2- yl)butanoyl]pyrrolidine-2- carboxamide 54

(M + 2H)⁺/ 2 = 538.8 (2S,4R)-N-({2-[2-(2-{3-[4-(3-{[(4,6-dimethyl-2-oxo-1,2- dihydropyridin-3- yl)methyl]carbamoyl}-5-[ethyl(oxan-4-yl)amino]-4- methylphenyl)phenoxy]propoxy}ethoxy)ethoxy]-4-(4-methyl- 1,3-thiazol-5- yl)phenyl}methyl)-4-hydroxy-1-[(2S)-3-methyl-2-(1-oxo-2,3- dihydro-1H-isoindol-2-yl)butanoyl]pyrrolidine-2- carboxamide 55

(M + 2H)⁺/ 2 = 590.8 (2S,4R)-N-({2-[2-(2-{4-[4-(3-{[(4,6-dimethyl-2-oxo-1,2- dihydropyridin-3- yl)methyl]carbamoyl}-5-[ethyl(oxan-4-yl)amino]-4- methylphenyl)phenoxy]butoxy}ethoxy)ethoxy]-4-(4-methyl- 1,3-thiazol-5- yl)phenyl}methyl)-4-hydroxy-1- [(2S)-3-methyl-2-(1-oxo-2,3- dihydro-1H-isoindol-2-yl)butanoyl]pyrrolidine-2- carboxamide 56

1122.4 (2S,4R)-N-{[2-(2-{3-[4-(3- {[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3- yl)methyl]carbamoyl}-5- [ethyl(oxan-4-yl)amino]-4-methylphenyl)phenoxy]propoxy} ethoxy)-4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}-4- hydroxy-1-[(2S)-3-methyl-2-(1-oxo-2,3-dihydro-1H-isoindol-2- yl)butanoyl]pyrrolidine-2- carboxamide 57

834.3 N-[(4,6-dimethyl-2-oxo-1,2- dihydropyridin-3-yl)methyl]-5-{4-[2-(2-{[2-(2,6- dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5- yl]oxy}ethoxy)ethoxy]phenyl}-3-[ethyl(oxan-4-yl)amino]-2- methylbenzamide 58

848.3 N-[(4,6-dimethyl-2-oxo-1,2- dihydropyridin-3-yl)methyl]-5-{4-[2-(3-{[2-(2,6- dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5- yl]oxy}propoxy)ethoxy]phenyl}-3-[ethyl(oxan-4-yl)amino]-2- methylbenzamide 59

1114.89 (2S,4R)-1-((S)-2-(2-(4-(4-(3′- (((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3- yl)methyl)carbamoyl)-5′- (ethyl(tetrahydro-2H-pyran-4-yl)amino)-4′-methyl-[1,1′- biphenyl]-4-yl)piperazin-1-yl)butoxy)acetamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)pyrrolidine-2-carboxamide 60

818.3 N-[(4,6-dimethyl-2-oxo-1,2- dihydropyridin-3-yl)methyl]-5-[4-(4-{[2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5- yl]oxy}butoxy)phenyl]-3- [ethyl(oxan-4-yl)amino]-2-methylbenzamide 61

(M + 2H)⁺/ 2 = 436.9 N-[(4,6-dimethyl-2-oxo-1,2- dihydropyridin-3-yl)methyl]-5- [4-(3-{4-[2-(2,6- dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5- yl]piperazin-1- yl}propoxy)phenyl]-3-[ethyl(oxan-4-yl)amino]-2- methylbenzamide 62

862.3 N-[(4,6-dimethyl-2-oxo-1,2- dihydropyridin-3-yl)methyl]-5-{4-[3-(3-{[2-(2,6- dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5- yl]oxy}propoxy)propoxy]pheny1}-3-[ethyl(oxan-4-yl)amino]-2- methylbenzamide 63

(M + 2H)⁺/ 2 = 546.9 (2S,4R)-N-[(2-{4-[4-(3-{[(4,6- dimethyl-2-oxo-1,2-dihydropyridin-3- yl)methyl]carbamoyl}-5- [ethyl(oxan-4-yl)amino]-4-methylphenyl)phenoxy]butoxy}- 4-(4-methyl-1,3-thiazol-5-yl)phenyl)methyl]-4-hydroxy- 1-[(2S)-3-methyl-2-(1-oxo-2,3-dihydro-1H-isoindol-2- yl)butanoyl]pyrrolidine-2- carboxamide 64

1064.4 N-[(2-{2-[4-(3-{[(4,6-dimethyl- 2-oxo-1,2-dihydropyridin-3-yl)methyl]carbamoyl}-5- [ethyl(oxan-4-yl)amino]-4-methylphenyl)phenoxy]ethoxy}- 4-(4-methyl-1,3-thiazol-5-yl)phenyl)methyl]-4-hydroxy- 1-[3-methyl-2-(1-oxo-2,3-dihydro-1H-isoindol-2- yl)butanoyl]pyrrolidine-2- carboxamide 65

N-((4,6-dimethyl-2-oxo-1,2- dihydropyridin-3-yl)methyl)-5-(2-(3-(4-(2-(2,6- dioxopiperidin-3-yl)-1,3- dioxoisoindolin-5-yl)piperazin-1- yl)propoxy)pyrimidin-5-yl)- 3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2- methylbenzamide 66

(2S,4R)-1-((S)-2-(5-(3-(6-(3- (((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3- yl)methyl)carbamoyl)-5- (ethyl(tetrahydro-2H-pyran-4-yl)amino)-4- methylphenyl)pyridin-3- yl)propoxy)pentanamido)-3,3-dimethylbutanoyl)-4- hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide 67

N-((4,6-dimethyl-2-oxo-1,2- dihydropyridin-3-yl)methyl)-4′-(4-(2-(2-((2-(2,6- dioxopiperidin-3-yl)-1,3- dioxoisoindolin-5-yl)oxy)ethoxy)ethyl)piperazin- 1-yl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4- methyl-[1,1′-biphenyl]-3- carboxamide 68

(2S,4R)-1-((S)-2-(2-(2-(2- ((5-(3-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3- yl)methyl)carbamoyl)-5-(ethyl(tetrahydro-2H-pyran- 4-yl)amino)-4- methylphenyl)pyridin-2-yl)oxy)ethoxy)ethoxy) acetamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4- methylthiazol-5- yl)phenyl)ethyl)pyrrolidine-2-carboxamide 69

(2S,4R)-1-((S)-2-(2-(2-(2-(4- (6-(3-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3- yl)methyl)carbamoyl)-5-(ethyl(tetrahydro-2H-pyran- 4-yl)amino)-4- methylphenyl)pyridin-3-yl)piperazin-l- yl)ethoxy)ethoxy)acetamido)- 3,3-dimethylbulanoyl)-4-hydroxy-N-(4-(4- methylthiazol-5- yl)benzyl)pyrrolidine-2- carboxamide70

(2S,4R)-1-((S)-2-(2-(2-(2- ((5-(3-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3- yl)methyl)carbamoyl)-5-(ethyl(tetrahydro-2H-pyran- 4-yl)amino)-4- methylphenyl)pyridin-2-yl)amino)ethoxy)ethoxy) acetamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4- methylthiazol-5- yl)phenyl)ethyl)pyrrolidine-2-carboxamide 71

(2S,4R)-1-((S)-2-(2-(2-(2-(4- (3′-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3- yl)methyl)carbamoyl)-5′-(ethyl(tetrahydro-2H-pyran- 4-yl)amino)-4′-methyl-[1,1′-biphenyl]-4-yl)piperazin-1- yl)ethoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4- hydroxy-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide 72

(2S,4R)-1-((S)-2-(2-(2-(2-(4- (3′-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3- yl)methyl)carbamoyl)-5′-(ethyl(tetrahydro-2H-pyran- 4-yl)amino)-4′-methyl-[1,1′-biphenyl]-4-yl)piperazin-1- yl)ethoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4- hydroxy-N-((S)-1-(4-(4- methylthiazol-5-yl)phenyl)ethyl)pyrrolidine- 2-carboxamide 73

N-((4,6-dimethyl-2-oxo-1,2- dihydropyridin-3-yl)methyl)-7-(6-((2-(2-(2-(((S)-1- ((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl- 1-oxobutan-2-yl)amino)-2-oxoethoxy)ethoxy)ethyl) amino)pyridin-3-yl)-2-methyl-1-(tetrahydro-2H-pyran-4-yl)- 1,2,3,4-tetrahydroquinoline- 5-carboxamide74

(2S,4R)-1-((S)-2-(2-(2-(2- ((3′-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5′-(((4- methoxy-6-methyl-2-oxo- 1,2-dihydropyridin-3-yl)methyl)carbamoyl)-4′- methyl-[1,1′-biphenyl]-4-yl)amino)ethoxy)ethoxy) acetamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4- methylthiazol-5- yl)phenyl)ethyl)pyrrolidine-2-carboxamide 75

N-((4,6-dimethyl-2-oxo-1,2- dihydropyridin-3-yl)methyl)-4′-(4-(2-(2-((2-(2,6- dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)oxy)ethoxy)ethyl)piperazin- 1-yl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4- methyl-[1,1′-biphenyl]-3- carboxamide 76

N-((4,6-dimethyl-2-oxo-1,2- dihydropyridin-3-yl)methyl)-4′-(4-(2-(2-((2-(2,6- dioxopiperidin-3-yl)-3- oxoisoindolin-5-yl)oxy)ethoxy)ethyl)piperazin- 1-yl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4- methyl-[1,1′-biphenyl]-3- carboxamide 77

(2S,4R)-1-((S)-2-(2-(2-((3- (3′-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5′-(((4- methoxy-6-methyl-2-oxo- 1,2-dihydropyridin-3-yl)methyl)carbamoyl)-4′- methyl-[1,1′-biphenyl]-4- yl)prop-2-yn-1-yl)oxy)ethoxy)acetamido)- 3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4- methylthiazol-5- yl)phenyl)ethyl)pyrrolidine-2-carboxamide 78

(2S,4R)-1-((S)-2-(2-(2-((3- (3′-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3- yl)methyl)carbamoyl)-5′-(ethyl(tetrahydro-2H-pyran- 4-yl)amino)-4′-methyl-[1,1′-biphenyl]-4-yl)prop-2-yn-1- yl)oxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4- hydroxy-N-((S)-1-(4-(4- methylthiazol-5-yl)phenyl)ethyl)pyrrolidine- 2-carboxamide 79

(2S,4R)-1-((S)-2-(2-(2-(4- (3′-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3- yl)methyl)carbamoyl)-5'-(ethyl(tetrahydro-2H-pyran- 4-yl)amino)-4′-methyl-[1,1′-biphenyl]-4-yl)-1H-l,2,3- triazol-1- yl)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4- hydroxy-N-((S)-1-(4-(4- methylthiazol-5-yl)phenyl)ethyl)pyrrolidine- 2-carboxamide 80

(2S.4R)-1-((S)-2-(2-(2-(2-(4- (3′-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3- yl)methyl)carbamoyl)-5′-(ethyl(tetrahydro-2H-pyran- 4-yl)amino)-4′-methyl-[1,1′-biphenyl]-4-yl)-1H-1,2,3- triazol-1- yl)ethoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4- hydroxy-N-((S)-l-(4-(4- methylthiazol-5-yl)phenyl)ethyl)pyrrolidine- 2-carboxamide 81

6-(2-(2-(2-(((S)-1-((2S,4R)- 4-hydroxy-2-(((S)-1-(4-(4- methylthiazol-5-yl)phenyl)ethyl)carbamoyl) pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2- oxoethoxy)ethoxy)ethoxy)-N-((4-methoxy-6-methyl-2- oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-((S)- 1-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-indole-3- carboxamide 82

6-(2-(2-(2-(((S)-1-((2S,4R)- 4-hydroxy-2-(((S)-1-(4-(4- methylthiazol-5-yl)phenyl)ethyl)carbamoyl) pyrrolidin-l-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2- oxoethoxy)ethoxy)ethoxy)-N-((4-methoxy-6-methyl-2- oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-((S)- 1-(1-(2,2,2- trifluoroethyl)piperidin-4-yl)ethyl)-1H-indole-3- carboxamide 93

(2S,4R)-1-((S)-2-(tert-butyl)- 14-(4-(3-chloro-4-(2-cyano-3-(pyridazin-4- yl)phenoxy)benzamido)- 2,2,6,6-tetramethylpiperidin-1-yl)-4-oxo-6,9,12-trioxa-3- azatetradecanoyl)-4-hydroxy-N-((S)-1-(4-(4- methylthiazol-5- yl)phenyl)ethyl)pyrrolidine-2-carboxamide 84

N-((4-ethyl-6-methyl-2-oxo- 1,2-dihydropyridin-3-yl)methyl)-6-(6-(4-((S)-13- ((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-carbonyl)- 14,14-dimethyl-11-oxo- 3,6,9-trioxa-12-azapentadecyl)piperazin-1- yl)pyridin-3-yl)-1-isopropyl-1H-indazole-4-carboxamide 85

1-((S)-sec-butyl)-N-((4,6- dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)- 6-(6-(4-((S)-13-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4- methylthiazol-5- yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-carbonyl)- 14,14-dimethyl-11-oxo- 3,6,9-trioxa-12-azapentadecyl)piperazin-1- yl)pyridin-3-yl)-1H- indazole-4-carboxamide86

6-(2-(2-(4-(2-(2,6- dioxopiperidin-3-yl)-1,3- dioxoisoindolin-5-yl)piperazin-1- yl)ethoxy)ethoxy)-N-((4- methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3- yl)methyl)-2-methyl-1-((S)-1-(tetrahydro-2H-pyran-4- yl)ethyl)-1H-indole-3- carboxamide 87

6-(4-(2-(2-((2-(2,6- dioxopiperidin-3-yl)-1,3- dioxoisoindolin-5-yl)oxy)ethoxy)ethyl)piperazin- 1-yl)-N-((4-methoxy-6- methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)- 2-methyl-1-((S)-1- (tetrahydro-2H-pyran-4-yl)ethyl)-1H-indole-3- carboxamide 88

1058.32 (2S,4R)-1-((S)-2-(5-(3-(3′- (((4,6-dimethyl-2-oxo-1,2-dibydropyridin-3- yl)methyl)carbamoyl)-5′- (ethyl(tetrahydro-2H-pyran-4-yl)amino)-41-methyl-[1,1′- biphenyl]-4- yl)propoxy)pentanamido)-3,3-dimethylbutanoyl)-4-hydroxy- N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2- carboxamide 89

1060.29 (2S,4R)-1-((S)-2-(2-(2-(3-(3- (((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3- yl)methyl)carbamoyl)-5′- (ethyl(tetrahydro-2H-pyran-4-yl)amino)-4′-methyl-[1,1′- biphenyl]-4- yl)propoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4- hydroxy-N-((S)-1-(4-(4- methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2- carboxamide 90

1078.12 (2S,4R)-N-(2-(3-((3′-(((4,6- dimethyl-2-oxo-1,2-dihydropyridin-3- yl)methyl)carbamoyl)-5′- (ethyl(tetrahydro-2H-pyran-4-yl)amino)-4′-methyl-[1,1′- biphenyl]-4-yl)oxy)propoxy)-4-(4-methylthiazol-5-yl)benzyl)- 4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2- yl)butanoyl)pyrrolidine-2- carboxamide 91

858.3 N-((4,6-dimethyl-2-oxo-1,2- dihydropyridin-3-yl)methyl)-4′-(2-(4-(2-(2,6-dioxopiperidin-3- yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethoxy)-5- (ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-[1,1′- biphenyl]-3-carboxamide 92

N-((4,6-dimethyl-2-oxo-1,2- dihydiopyridin-3-yl)methyl)-4′-(4-(4-(2-(2,6-dioxopiperidin-3- yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)butoxy)-5- (ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-[1,1′- biphenyl]-3-carboxamide 93

523.8 [M/2 + H) (2S,4R)-1-((S)-2-(2-(4-((3- (((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3- yl)methyl)carbamoyl)-5′- (ethyl(tetrahydro-2H-pyran-4-yl)amino)-4′-methyl-[1,1′- biphenyl]-4- yl)oxy)butoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy- N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2- carboxamide 94

1060.5 (2S,4R)-1-((S)-2-(2-((5-((3′- (((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3- yl)methyl)carbamoyl)-5′- (ethyl(tetrahydro-2H-pyran-4-yl)amino)-4′-methyl-[1,1′- biphenyl]-4- yl)oxy)pentyl)oxy)acetamido)-3,3-dimethylbutanoyl)-4- hydroxy-N-((S)-1-(4-(4- methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2- carboxamide 95

1032.4 (2S,4R)-1-((S)-2-(2-(3-((3′- (((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3- yl)methyl)carbamoyl)-5′- (ethyl(tetrahydro-2H-pyran-4-yl)amino)-4′-methyl-[1,1′- biphenyl]-4- yl)oxy)propoxy)acetamido)-3,3-dimethylbutanoyl)-4- hydroxy-N-((S)-1-(4-(4- methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2- carboxamide 96

(2R,4S)-1-((S)-2-(2-(2-(2-((3′- (((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3- yl)methyl)carbamoyl)-5′- (ethyl(tetrahydro-2H-pyran-4-yl)amino)-4′-methyl-[1,1′- biphenyl]-4- yl)oxy)ethoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4- hydroxy-N-((S)-1-(4-(4- methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2- carboxamide 97

1092.48 (2S,4R)-1-((R)-2-(6-(3-((3′- (((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3- yl)methyl)carbamoyl)-5′- (ethyl(tetrahydro-2H-pyran-4-yl)amino)-4′-methyl-[1,1′- biphenyl]-4-yl)oxy)propoxy)-1-oxoisoindolin-2-yl)-3- methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)pyrrolidine-2- carboxamide98

1092.48 (2S,4R)-1-((S)-2-(6-(3-((3′- (((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3- yl)methyl)carbamoyl)-5′- (ethyl(tetrahydro-2H-pyran-4-yl)amino)-4′-methyl-[1,1′- biphenyl]-4-yl)oxy)propoxy)-1-oxoisoindolin-2-yl)-3- methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)pyrrolidine-2- carboxamide99

1092.48 (2S,4R)-1-((S)-2-(6-(2-((3′- (((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3- yl)methyl)carbamoyl)-5′- (ethyl(tetrahydro-2H-pyran-4-yl)amino)-4′-methyl-[1,1′- biphenyl]-4- yl)methoxy)ethoxy)-1-oxoisoindolin-2-yl)-3- methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)pyrrolidine-2- carboxamide100

1078.47 (2S,4R)-1-((S)-2-(6-(2-((3- (((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3- yl)methyl)carbamoyl)-5′- (ethyl(tetrahydro-2H-pyran-4-yl)amino)-4′-methyl-[1,1′- biphenyl]-4-yl)oxy)ethoxy)-1-oxoisoindolin-2-yl)-3- methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)pyrrolidine-2- carboxamide101

1106.49 (2S,4R)-1-((R)-2-(6-(4-((3′- (((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3- yl)methyl)carbamoyl)-5′- (ethyl(tetrahydro-2H-pyran-4-yl)amino)-4′-methyl-[1,1′- biphenyl]-4-yl)oxy)butoxy)-1-oxoisoindolin-2-yl)-3- methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)pyrrolidine-2- carboxamide102

1106.49 (2S,4R)-1-((S)-2-(6-(4-((3- (((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3- yl)methyl)carbamoyl)-5′- (ethyl(tetrahydro-2H-pyran-4-yl)amino)-4′-methyl-[1,1′- biphenyl]-4-yl)oxy)butoxy)-1-oxoisoindolin-2-yl)-3- methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)pyrrolidine-2- carboxamide103

1106.49 (2S,4R)-1-(2-(6-(4-((3′-(((4,6- dimethyl-2-oxo-1,2-dihydropyridin-3- yl)methyl)carbamoyl)-5′- (ethyl(tetrahydro-2H-pyran-4-yl)amino)-4′-methyl-[1,1′- biphenyl]-4-yl)oxy)butoxy)-1-oxoisoindolin-2-yl)-3- methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)pyrrolidine-2- carboxamide104

1056.47 (2S,4R)-1-(2-(3-((5-((3′-(((4,6- dimethyl-2-oxo-1,2-dihydropyridin-3- yl)methyl)carbamoyl)-5′- (ethyl(tetrahydro-2H-pyran-4-yl)amino)-4′-methyl-[1,1′- biphenyl]-4- yl)oxy)pentyl)oxy)isoxazol-5-yl)-3-methylbutanoyl)-4- hydroxy-N-((S)-1-(4-(4- methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2- carboxamide 105

1058.45 (2S,4R)-1-(2-(3-(2-(2-((3- (((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3- yl)methyl)carbamoyl)-5′- (ethyl(tetrahydro-2H-pyran-4-yl)amino)-4′-methyl-[1,1′- biphenyl]-4- yl)oxy)ethoxy)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4- hydroxy-N-((S)-1-(4-(4- methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2- carboxamide 106

1070.49 (2S,4R)-1-(2-(3-((6-((3′-(((4,6- dimethyl-2-oxo-1,2-dihydropyridin-3- yl)methyl)carbamoyl)-5′- (ethyl(tetrahydro-2H-pyran-4-yl)amino)-4′-methyl-[1,1′- biphenyl]-4- yl)oxy)hexyl)oxy)isoxazol-5-yl)-3-methylbutanoyl)-4- hydroxy-N-((S)-1-(4-(4- methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2- carboxamide 107

1042.46 (2S,4R)-1-(2-(3-(4-((3′-(((4,6- dimethyl-2-oxo-1,2-dihydropyridin-3- yl)methyl)carbamoyl)-5′- (ethyl(tetrahydro-2H-pyran-4-yl)amino)-4′-methyl-[1,1′- biphenyl]-4- yl)oxy)butoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N- ((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2- carboxamide 108

1092.37 (2S,4R)-1-((S)-2-(6-((2-((3′- (((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3- yl)methyl)carbamoyl)-5′- (ethyl(tetrahydro-2H-pyran-4-yl)amino)-4′-methyl-[1,1′- biphenyl]-4- yl)oxy)ethoxy)methyl)-1-oxoisoindolin-2-yl)-3- methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)pyrrolidine-2- carboxamide109

1072.38 (2S,4R)-1-(2-(3-(3-(2-((3- (((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3- yl)methyl)carbamoyl)-5′- (ethyl(tetrahydro-2H-pyran-4-yl)amino)-4′-methyl-[1,1′- biphenyl]-4- yl)oxy)ethoxy)propoxy)isoxazol-5-yl)-3-methylbutanoyl)-4- hydroxy-N-((S)-1-(4-(4- methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2- carboxamide 110

1042.37 (2S,4R)-1-(2-(3-(2-(2-(3′-(((4,6- dimethyl-2-oxo-1,2-dihydropyridin-3- yl)methyl)carbamoyl)-5′- (ethyl(tetrahydro-2H-pyran-4-yl)amino)-4′-methyl-[1,1′- biphenyl]-4- yl)ethoxy)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4- hydroxy-N-((S)-1-(4-(4- methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2- carboxamide 111

1056.39 (2S,4R)-1-(2-(3-(2-(3-(3′-(((4,6- dimethyl-2-oxo-1,2-dihydropyridin-3- yl)methyl)carbamoyl)-5′- (ethyl(tetrahydro-2H-pyran-4-yl)amino)-4′-methyl-[1,1′- biphenyl]-4- yl)propoxy)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4- hydroxy-N-((S)-1-(4-(4- methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2- carboxamide 112

1072.39 (2S,4R)-1-(2-(3-(2-(3-((3- (((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3- yl)methyl)carbamoyl)-5′- (ethyl(tetrahydro-2H-pyran-4-yl)amino)-4′-methyl-[1,1′- biphenyl]-4- yl)oxy)propoxy)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4- hydroxy-N-((S)-1-(4-(4- methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2- carboxamide 113

925.73 N-((4,6-dimethyl-2-oxo-1,2- dihydropyridin-3-yl)methyl)-4′-((4-((1-(2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4- yl)methyl)piperazin-1- yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4- methyl-[1,1′-biphenyl]-3- carboxamide 114

1144.90 (2S,4R)-1-((S)-2-(2-(2-(2-(4- ((3′-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3- yl)methyl)carbamoyl)-5′- (ethyl(tetrahydro-2H-pyran-4-yl)amino)-4′-methyl-[1,1′- biphenyl]-4- yl)methyl)piperazin-1-yl)ethoxy)ethoxy) acetamido)- 3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4- methylthiazol-5- yl)phenyl)ethyl)pyrrolidine-2-carboxamide 115

925.73 N-((4,6-dimethyl-2-oxo-1,2- dihydiopyridin-3-yl)methyl)-4′-((4-((4-(2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1- yl)methy l)piperidin-1- yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4- methyl-[1,1′-biphenyl]-3- carboxamide 116

1100.86 (2S,4R)-1-((S)-2-(2-(2-(4-((3′- (((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3- yl)methyl)carbamoyl)-5′- (ethyl(tetrahydro-2H-pyran-4-yl)amino)-4′-methyl-[1,1′- biphenyl]-4- yl)methyl)piperazin-1-yl)ethoxy)acetamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)pyrrolidine-2-carboxamide 117

1128.90 (2S,4R)-1-((S)-2-(2-(4-(4-((3′- (((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3- yl)methyl)carbamoyl)-5′- (ethyl(tetrahydro-2H-pyran-4-yl)amino)-4′-methyl-[1,1′- biphenyl]-4- yl)methyl)piperazin-1-yl)butoxy)acetamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)pyrrolidine-2-carboxamide 118

1114.89 (2S,4R)-1-((S)-2-(2-(3-(4-((3′- (((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3- yl)methyl)carbamoyl)-5′- (ethyl(tetrahydro-2H-pyran-4-yl)amino)-4′-methyl-[1,1′- biphenyl]-4- yl)methyl)piperazin-1-yl)propoxy)acetamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)pyrrolidine-2-carboxamide 119

1144.90 (2S,4R)-1-((S)-2-(2-(2-(3-(4- (3′-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3- yl)methyl)carbamoyl)-5′- (ethyl(tetrahydro-2H-pyran-4-yl)amino)-4′-methyl-[1,1′- biphenyl]-4-yl)piperazin-1-yl)propoxy)ethoxy)acetamido)- 3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4- methylthiazol-5- yl)phenyl)ethyl)pyrrolidine-2-carboxamide

The following PROTACs demonstrated target protein degradation whentested under the conditions described above:

The following PROTACs demonstrated target protein degradation whentested under the conditions described above:

TABLE 2 Target protein degradation via Exemplary PROTACs Synthetic Ex #DC₅₀ 1H NMR Scheme 1 B 2 B 3 B 4 B 5 B 6 B 7 B 3 8 B 4 9 B 4 10 B ¹HNMR(400 MHz, CDCl₃): δ 11.40 (s, 1H), 7.88 (s, 1H), 3 7.35-7.50 (m, 3H),7.09 (d, J = 6.8 Hz, 3H), 6.90 (d, J = 8.4 Hz, 1H), 6.51 (s, 1H),4.88-4.91 (t, 1H), 4.10-4.59 (m, 6H), 3.44-3.68 (m, 16H), 2.65-2.83 (m,11H), 2.43 (s, 3H), 1.67-2.20 (m, 6H), 1.59-1.61 (m, 4H). 11 B 4 12 B¹HNMR (400 MHz, CDCl₃): δ 11.12 (br, 1H), 7.87 (s, 1H), 3 7.45 (m, 2H),7.35 (m, 1H), 7.15 (m, 3H), 6.91 (d, J = 8.8 Hz, 1H), 6.51 (s, 1H), 5.92(s, 1H), 4.90 (m, 1H), 4.52 (m, 3H), 4.09 (m, 3H), 3.53 (m, 20H), 2.75(m, 8H), 2.43 (s, 3H), 2.20 (s, 3H), 2.10 (m, 3H), 1.60 (m, 5H). 13 B 214 B 2 15 B 2 16 B 2 17 B 1 18 B 1 19 B 1 20 B 1 21 B H-NMR (300 MHz,CD3OD) δ 7.55-7.43 (m, 2H), 7.32-7.29 (m, 1 2H), 7.14-7.01 (s, 4H),6.92-6.89 (m, 1H), 6.10 (s, 1H), 5.01-4.99 (m, 1H), 4.49 (s, 2H),4.18-4.15 (m, 2H), 3.95-3.78 (m, 4H), 3.75-3.51 (m, 18H), 3.51-3.33 (m,4H), 3.22-3.01 (m, 3H), 2.89-2.59 (m, 3H), 2.39 (s, 3H), 2.33 (s, 3H),2.23 (s, 3H), 2.12-2.02 (m, 1H), 1.82-1.55 m, 4H), 0.92-081 (m, 3H) 22 BH-NMR: (300 MHz, CD3OD) δ 7.57-7.50 (m, 3H), 7.43 (s, 1 1H), 7.29 (s,1H), 7.10-6.99 (m, 4H), 6.13 (s, 1H), 5.07-4.89 (m, 1H), 4.51 (s, 2H),4.18-4.15 (m, 2H), 3.95-3.92 (d, J = 11.2 Hz, 2H), 3.88-3.86 (m, 2H),3.72-3.60 (m, 26H), 3.51-3.48 (m, 2H), 3.45-3.40 (m, 2H), 3.19-3.11 (m,3H), 2.82-2.72 (m, 3H), 2.41 (s, 3H), 2.33 (s, 3H), 2.25 (s, 3H),2.09-2.07 (m, 1H), 1.79-1.76 (m, 2H), 1.66-1.64 (m, 2H), 0.93-0.89 (m,3H) 23 B H-NMR: (400 MHz, CD3OD) δ 7.58-7.50 (m, 3H), 7.43 (s, 1 1H),7.29 (s, 1H), 7.11-7.00 (m, 4H), 6.13 (s, 1H), 5.07-5.02 (m, 1H), 4.51(s, 2H), 4.18-4.16 (m, 2H), 3.95-3.92 (d, J = 10.4 MHz, 2H), 3.88-3.86(m, 2H), 3.73-3.60 (m, 30H), 3.51-3.49 (m, 2H), 3.41-3.37 (m, 2H),3.19-3.14 (m, 3H), 2.91-2.67 (m, 3H), 2.41 (s, 3H), 2.33 (s, 3H), 2.56(s, 3H), 2.11-2.03 (m, 1H), 1.79-1.76 (d, J = 12.4 MHz, 2H), 1.67-1.64(m, 2H), 0.93-0.90 (m, 3H) 24 B ¹H NMR (300 MHz, CD₃OD) δ11.60 (s, 1H),10.41 (s, 1H), 5 8.62-8.55 (m, 1H), 8.33-8.31 (m, 1H), 8.19-8.16 (m,1H), 7.82-7.80 (m, 1H), 7.60-7.54 (m, 6H), 7.40-7.35 (m, 4H), 7.18 (s,1H), 7.02-6.99 (m, 2H), 5.85 (s, 1H), 4.61-4.59 (m, 2H), 4.50-4.25 (m,3H), 4.11-4.10 (m, 2H), 4.08-3.91 (m, 4H), 3.91-3.72 (m, 4H), 3.56-3.54(m, 10H), 3.42-3.34 (m, 4H), 3.08-3.06 (m, 3H), 2.51-2.49 (m, 6H), 2.10(s, 3H), 1.75-1.63 (m, 4H), 0.97 (s, 9H). 25 B H-NMR (400 MHz, CD3OD) δ7.55-7.43 (m, 2H), 7.32-7.22 (m, 1 3H), 7.14-7.01 (s, 4H), 6.10 (s, 1H),5.01-4.99 (m, 1H), 4.49 (s, 2H), 4.18-4.15 (m, 2H), 3.95-3.89 (m, 2H),3.75-3.68 (m, 4H), 3.66-3.50 (m, 18H), 3.22-3.01 (m, 3H), 2.89-2.59 (m,3H), 2.39 (s, 3H), 2.33 (s, 3H), 2.23 (s, 3H), 2.12-2.02 (m, 3H),1.82-1.55 m, 4H), 0.91-0.89 (m, 3H) 26 B 1H NMR (400 MHz, CD₃OD):δ7.52-7.49 (d, J = 8.8 Hz, 2H), 6 7.42 (d, J = 1.6 Hz, 1H), 7.29 (s,1H), 7.09-6.99 (m, 4H), 6.85-6.83 (m, 2H), 6.12 (s, 1H), 4.50 (s, 2H),4.16-4.14 (m, 3H), 4.09-4.07 (m, 2H), 3.94-3.82 (m, 7H), 3.74 (m, 4H),3.37-3.32 (m, 3H), 3.16-3.13 (m, 5H), 2.85-2.70 (m, 3H), 2.60-2.50 (m,2H), 2.33-2.30 (m, 3H), 2.28-2.26 (m, 6H), 2.25 (s, 3H), 2.20-2.00 (m,4H), 1.88-1.85 (m, 3H), 1.78-1.64 (m, 10H), 1.24-1.21 (d, J = 14.0 Hz,6H), 1.20-1.00 (m, 2H), 0.92-0.89 (t, J = 7.0 Hz, 3H) 27 B 1H NMR (400MHz, CD3OD): δ8.38-8.36 (d, J = 8.4 Hz, 1H), 5 7.72-7.70 (m, 1H),7.56-7.47 (m, 4H), 7.45-7.33 (m, 4H), 7.29-7.24 (m, 3H), 7.00-6.98 (d, J= 8.8 Hz, 2H), 6.11 (s, 1H), 4.78-4.75 (d, J = 8.4 Hz, 1H), 4.63-4.61(d, J = 9.6 Hz, 1H), 4.50 (s, 2H), 4.15-4.12 (m, 2H), 4.09-4.06 (d, J =9.6 Hz, 1H), 3.99 (s, 3H), 3.94-3.82 (m, 4H), 3.69-3.55 (m, 20H),3.39-3.36 (m, 2H), 3.16-3.14 (m, 3H), 2.40 (s, 3H), 2.32 (s, 3H), 2.24(s, 3H), 1.74-1.68 (m, 5H), 1.38-1.35 (m, 1H), 1.04 (s, 9H), 0.92-0.88(m, 3H) 28 B ¹H NMR (400 MHz, CD₃OD): δ 8.35 (m, 1H), 8.10 (m, 1H), 77.50-7.43 (m, 6H), 7.38 (s, 1H), 7.25 (m, 1H), 6.95-6.92 (m, 3H), 6.09(s, 1H), 5.50 (m, 1H), 4.60 (m, 1H), 4.48 (s, 2H), 4.34-4.32 (d, J =4.40 Hz, 2H), 4.10-4.08 (m, 2H), 4.03-4.01 (m, 2H), 3.90-3.76 (m, 10H),3.32-3.30 (m, 3H), 3.20-3.10 (m, 4H), 2.38 (s, 3H), 2.33-2.30 (d, J =11.2 Hz, 6H), 2.22-2.16 (m, 4H), 1.80-1.59 (m, 11H), 1.28-1.24 (m, 5H),1.13-1.11 (m, 4H), 0.88-0.85 (t, J = 7.0 Hz, 3H) 29 B 1H NMR (400 MHz,CD3OD): δ7.60-7.50 (m, 2H), 7.41-7.40 (s, 6 1H), 7.27 (s, 1H), 7.19-6.98(m, 4H), 6.90-6.83 (m, 2H), 6.11 (m, 1H), 4.88 (s, 2H), 4.49 (m, 1H),4.14-4.05 (m, 5H), 4.05-3.79 (m, 7H), 3.70-3.64 (m, 13H), 3.35-3.30 (s,1H), 3.15-3.00 (m, 4H), 2.80-2.60 (m, 3H), 2.60-2.50 (m, 3H), 2.45-2.35(m, 3H), 2.30 (s, 6H), 2.24-2.10 (m, 5H), 2.10-1.95 (m, 2H), 1.90-1.50(m, 14H), 1.40-1.15 (m, 10H), 0.91-0.85 (m, 3H) 30 B 1H NMR (400 MHz,CD3OD): δ 8.40 (m, 1H), 8.10-8.00 (m, 7 1H), 7.60-7.45 (m, 7H), 7.39 (s,1H), 7.26 (s, 1H), 6.95-6.93 (m, 3H), 6.09 (s, 1H), 5.50 (s, 1H), 4.60(m, 1H), 4.48 (s, 2H), 4.32 (m, 2H), 4.08-4.07 (m, 2H), 4.00-3.99 (m,3H), 3.98-3.90 (m, 3H), 3.78-3.77 (m, 5H), 3.76-3.75 (m, 3H), 3.69-3.60(m, 10H), 3.30-3.12 (m, 4H), 2.40-2.38 (m, 7H), 2.30 (s, 4H), 2.22 (s,6H), 2.15-2.00 (m, 2H), 1.90-1.50 (m, 12H), 0.89-0.85 (m, 4H) 31 A ¹HNMR(400 MHz, MeOD): δ 8.81 (s, 1H), 7.36-7.45 (m, 7H), 2 6.96 (d, J = 8.8Hz, 2H), 6.10 (s, 1H), 4.85 (s, 1H), 4.49-4.69 (m, 5H), 4.18-4.19 (d, J= 4.8 Hz, 1H), 4.05-4.17 (m, 4H), 3.75-3.91 (m, 10H), 3.11-3.13 (m, 3H),2.41 (s, 3H), 2.39 (s, 3H), 2.30 (s, 3H), 2.03-2.23 (m, 7H), 1.50-1.80(m, 5H), 1.00 (s, 9H), 0.88 (m, 6H). 32 B ¹H NMR (400 MHz, MeOD): δ 8.77(s, 1H), 7.32-7.48 (m, 7H), 2 7.21 (s, 1H), 7.10 (d, J = 8.8 Hz, 2H),6.10 (s, 1H), 4.73 (s, 1H), 4.49-4.62 (m, 5H), 3.80-4.35 (m, 11H),2.92-3.11 (m, 3H), 2.47 (s, 3H), 2.39 (s, 3H), 2.35 (s, 3H), 2.30 (s,3H), 2.10-2.28 (m, 7H), 1.50-1.80 (m, 4H), 1.36 (s, 9H), 0.82-0.93 (m,3H). 33 B ¹HNMR (400 MHz, CDCl₃): δ 10.98 (s, 1H), 10.75 (s, 1H), 1 7.46(m, 4H), 7.27 (m, 1H), 7.20 (s, 1H), 7.08 (d, J = 7.2 Hz, 1H), 6.95 (d,J = 8.8 Hz, 2H), 6.89 (d, J = 8.4 Hz, 1H), 6.60 (m, 1H), 5.92 (s, 1H),4.80 (m, 2H), 4.51 (d, J = 6.0 Hz, 2H), 4.15-4.30 (m, 2H), 3.65-4.00 (m,10H), 3.00-3.55 (m, 7H), 2.50-2.75 (m, 3H), 2.42 (s, 3H), 2.38 (s, 3H),2.20 (s, 3H), 1.90 (m, 1H), 1.75 (m, 3H), 0.89 (m, 3H). 34 B ¹H NMR (400MHz, MeOD): δ11.55 (br, 1H), 10.85 (br, 1H), 1 7.42-7.56 (m, 5H), 7.29(s, 1H), 7.22 (s, 1H), 7.10 (d, J = 7.2 Hz, 1H), 7.06 (d, J = 28.2 Hz,2H), 6.95 (m, 1H), 6.71 (m, 1H), 5.91 (s, 1H), 4.92-4.98 (m, 1H),4.65-4.72 (m, 1H), 4.35-4.41 (m, 1H), 4.19-4.21 (m, 2H), 3.81-3.96 (m,6H), 3.21-3.47 (m, 4H), 2.83-3.17 (m, 6H), 2.41 (s, 6H), 2.19 (s, 3H),2.12-2.23 (m, 1H), 1.71 (m, 3H), 0.89 (t, J = 14.0 Hz, 3H). 35 B ¹H NMR(400 MHz, DMSO): δ 11.42 (s, 1H), 8.90 (s, 1H), 8 8.29 (s, 1H), 8.10 (s,1H), 7.54 (d, J = 3.2 Hz, 1H), 7.45-7.55 (m, 5H), 7.27 (d, J = 5.6 Hz,2H), 7.11 (s, 1H), 6.92-6.98 (m, 4H), 5.78 (s, 1H), 5.02 (s, 1H), 4.67(d, J = 4.0 Hz, 1H), 4.32-4.51 (m, 3H), 4.22-4.28 (m, 5H), 4.05-4.12 (m,4H), 3.67-3.72 (m, 8H), 3.46-4.50 (m, 12H), 3.11 (m, 3H), 3.05 (m, 3H),2.40 (s, 3H), 2.25 (m, 1H), 2.16 (s, 3H), 2.14 (s, 3H), 2.03 (s, 3H),2.00 (m, 1H), 1.90 (m, 1H), 1.61 (m, 2H), 1.52 (m, 2H), 0.90 (d, J = 6.4Hz, 3H), 0.75 (t, J = 6.8 Hz, 3H), 0.66 (d, J = 6.8 Hz, 3H). 36 B ¹HNMR(400 MHz, DMSO): δ 11.45 (s, 1H), 8.99 (s, 1H), 8 8.38 (t, J = 6.4 Hz,1H), 8.18 (t, J = 6.4 Hz, 1H), 7.75 (d, J = 4.8 Hz, 1H), 7.60 (m, 5H),7.40 (m, 2H), 7.15 (s, 1H), 7.02 (m, 4H), 5.88 (s, 1H), 5.12 (s, 1H),4.72 (d, J = 4.0 Hz, 1H), 4.40 (m, 12H), 3.50 (m, 16H), 3.25 (m, 3H),3.10 (m, 3H), 2.42 (d, J = 14.4 Hz, 3H), 2.30 (m, 1H), 2.15 (d, J = 10.4Hz, 3H), 2.15 (s, 3H), 1.90 (m, 2H), 1.50 (m, 4H), 1.00 (d, J = 6.4 Hz,3H), 0.85 (t, J = 6.8 Hz, 3H), 0.76 (d, J = 6.8 Hz, 3H). 37 A ¹HNMR (400MHz, CD3OD): δ 8.84 (s, 1H), 7.81 (t, J = 6.8 Hz, 8 1H), 7.41-7.53 (m,7H), 7.24 (s, 1H), 7.03-7.04 (m, 2H), 6.94 (d, J = 8.8 Hz, 2H), 6.08 (s,1H), 5.12 (s, 1H), 4.45-4.57 (m, 8H), 4.22-4.24 (m, 2H), 4.09-4.22 (m,2H), 3.74-3.92 (m, 12H), 3.11-3.13 (m, 3H), 2.47 (s, 3H), 2.38 (s, 3H),2.31 (m, 3H), 2.22 (s, 3H), 2.15 (m, 13H), 2.04 (m, 1H), 1.60-1.72 (m,4H), 1.03 (d, J = 6.4 Hz, 3H), 0.88 (t, J = 6.8 Hz, 3H), 0.80 (d, J =6.8 Hz, 3H). 38 B ¹H NMR (400 MHz, CD3OD): δ 8.84 (s, 1H), 7.74 (t, J =6.8 Hz, 8 1H), 7.38-7.57 (m, 8H), 7.25 (s, 1H), 7.02-7.06 (m, 2H), 6.96(d, J = 8.8 Hz, 2H), 6.08 (s, 1H), 4.42-4.55 (m, 9H), 4.27 (s, 2H), 4.19(s, 2H), 3.89-3.99 (m, 9H), 3.12-3.14 (m, 3H), 2.47 (s, 3H), 2.38 (s,3H), 2.31 (m, 3H), 2.22 (s, 3H), 2.15 (m, 1H), 2.04 (m, 1H), 1.60-1.72(m, 4H), 1.03 (d, J = 6.4 Hz, 3H), 0.88 (t, J = 6.8 Hz, 3H), 0.80 (d, J= 6.8 Hz, 3H). 39 B 1H NMR (400 MHz, DMSO): δ 11.45 (s, 1H), 8.99 (s,1H), 8 8.38 (t, J = 6.4 Hz, 1H), 8.18 (t, J = 6.4 Hz, 1H), 7.75 (d, J =4.8 Hz, 1H), 7.60 (m, 5H), 7.35 (m, 2H), 7.18 (s, 1H), 6.99 (m, 4H),5.86 (s, 1H), 5.09 (s, 1H), 4.72 (d, J = 4.0 Hz, 1H), 4.40 (m, 12H),3.80 (m, 4H), 3.00-3.60 (m, 14H), 2.45 (s, 3H), 2.35 (m, 1H), 2.24 (s,3H), 2.21 (s, 3H), 2.11 (s, 3H), 1.95 (m, 6H), 1.50-1.80 (m, 6H), 1.30(d, J = 12.0 Hz, 2H), 0.97 (d, J = 6.8 Hz, 3H), 0.83 (t, J = 6.8 Hz,3H), 0.74 (d, J = 6.8 Hz, 3H). 40 B ¹HNMR (400 MHz, DMSO): δ 11.45 (s,1H), 8.97 (s, 1H), 8 8.33-8.35 (m, 1H), 8.13-8.15 (m, 1H), 7.70 (t, J =6.8 Hz, 1H), 7.61 (d, J = 4.0 Hz, 2H), 7.50-7.52 (m, 3H), 7.33 (m, 2H),7.16 (s, 1H), 6.95-7.02 (m, 4H), 5.85 (s, 1H), 5.08 (s, 1H), 4.71 (d, J= 6.8 Hz, 1H), 4.41-4.52 (m, 3H), 4.31-4.41 (s, 5H), 4.20 (t, J = 4.0Hz, 2H), 3.98 (t, J = 4.0 Hz, 2H), 3.59-3.78 (m, 4H), 3.47 (t, J = 6.4Hz, 3H), 3.31 (t, J = 6.4 Hz, 2H), 2.46 (s, 3H), 2.21-2.23 (m, 6H), 2.10(m, 3H), 1.95-2.00 (m, 3H), 1.64-1.82 (m, 6H), 1.45-1.52 (m, 2H), 0.96(d, J = 6.4 Hz, 3H), 0.82 (t, J = 6.8 Hz, 3H), 0.73 (t, J = 6.4 Hz, 3H).41 A ¹HNMR (400 MHz, MeOD): δ 8.83 (s, 1H), 7.80 (d, J = 8.0 Hz, 2 1H),7.44-7.47 (m, 5H), 7.36-7.38 (m, 2H), 7.24 (s, 1H), 7.01 (d, J = 8.0 Hz,2H), 6.11 (s, 1H), 4.50-4.57 (m, 9H), 4.32-4.35 (m, 1H), 4.17-4.19 (m,2H), 4.02-4.04 (m, 2H), 3.88-3.92 (m, 3H), 3.78-3.83 (m, 3H), 3.05-3.15(m, 3H), 2.42 (s, 3H), 2.40 (s, 3H), 2.32 (s, 3H), 2.21-2.24 (m, 4H),2.10-2.15 (m, 3H), 1.72-1.78 (m, 2H), 1.61-1.69 (m, 2H), 1.03 (s, 9H),0.89 (t, J = 4.0 Hz, 3H). 42 A ¹HNMR (400 MHz, CDCl3): δ 10.51 (br, 1H),8.67 (s, 1H), 2 7.42 (d, J = 8.4 Hz, 2H), 7.26-7.43 (m, 8H), 7.21 (s,2H), 6.91 (d, J = 8.4 Hz, 2H), 5.90 (s, 1H), 4.72 (t, J = 6.4 Hz, 1H),4.52-4.59 (m, 4H), 4.40-4.45 (m, 1H), 4.23-4.28 (m, 1H), 3.91-4.05 (m,6H), 3.57-3.62 (m, 3H), 3.22-3.28 (m, 2H), 2.95-3.07 (m, 3H), 2.50 (s,4H), 2.41 (s, 3H), 2.35 (s, 3H), 2.19 (s, 3H), 1.95-2.07 (m, 2H),1.81-1.87 (m, 4H), 1.62-1.69 (m, 3H), 0.95 (s, 9H), 0.89 (t, J = 6.8 Hz,3H). 43 A ¹HNMR (400 MHz, CDCl₃) δ 10.53 (br, 2H), 8.67 (s, 1H), 27.41-7.54 (m, 4H), 7.35 (dd, J = 17.5, 8.2 Hz, 4H), 7.28 (s, 1H), 7.20(s, 1H), 6.99 (d, J = 8.5 Hz, 2H), 5.90 (s, 1H), 5.01-5.12 (m, 1H), 4.75(t, J = 7.6 Hz, 1H), 4.70 (d, J = 8.9 Hz, 1H), 4.62 (dd, J = 14.1, 6.4Hz, 1H), 4.51 (s, 1H), 4.39 (dd, J = 14.3, 5.4 Hz, 1H), 4.31 (s, 1H),4.19 (d, J = 11.1 Hz, 3H), 4.10-3.98 (m, 2H), 3.97-3.83 (m, 5H), 3.75(d, J = 4.2 Hz, 2H), 3.65-3.72 (m, 2H), 3.58 (d, J = 8.6 Hz, 1H), 3.31(s, 2H), 3.08 (d, J = 6.8 Hz, 2H), 3.00 (s, 1H), 2.51 (s, 3H), 2.43 (s,3H), 2.36 (s, 3H), 2.19 (s, 3H), 1.95-2.05 (m, 1H), 1.44 (d, J = 6.9 Hz,3H), 1.07 (s, 9H), 0.87 (t, J = 6.9 Hz, 3H). 44 B ¹HNMR (400 MHz, MeOD):δ 8.84 (s, 1H), 7.80 (d, J = 8.0 Hz, 9 1H), 7.38-7.47 (m, 7H), 7.24-7.29(m, 3H), 6.09 (s, 1H), 4.62-4.65 (m, 1H), 4.54-4.56 (m, 1H), 4.43-4.48(m, 3H), 4.32-4.35 (m, 1H), 3.88-3.91 (m, 3H), 3.73-3.75 (m, 1H), 3.65(s, 1H), 3.40-3.44 (m, 4H), 3.32-3.35 (m, 2H), 3.10-3.14 (m, 3H),2.65-2.70 (m, 2H), 2.45 (s, 3H), 2.38 (s, 3H), 2.29-2.31 (m, 5H),2.21-2.23 (m, 4H), 2.16-2.18 (m, 1H), 1.86-1.88 (m, 2H), 1.72-1.78 (m,4H), 1.61-1.69 (m, 4H), 1.03 (s, 9H), 0.89 (t, J = 4.0 Hz, 3H). 45 B ¹HNMR (400 MHz, CDCl₃): δ 11.13 (br, 1H), 8.60 (s, 1H), 2 7.32-7.37 (m,4H), 7.19-7.25 (m, 6H), 7.14 (s, 1H), 6.87 (d, J = 8.0 Hz, 2H), 5.83 (s,1H), 5.22 (s, 2H), 4.43-4.58 (m, 5H), 4.28-4.33 (m, 1H), 4.18-4.23 (m,1H), 3.93-4.12 (m, 3H), 3.85-3.89 (m, 4H), 3.53-3.59 (m, 7H), 3.21-3.25(m, 2H), 2.93-3.02 (m, 3H), 2.43 (s, 3H), 2.30-2.34 (m, 7H), 2.10 (s,3H), 1.95-1.98 (m, 3H), 1.19 (s, 3H), 0.89 (s, 9H), 0.81 (t, J = 6.8 Hz,3H). 46 A ¹HNMR (400 MHz, CDCl₃): δ 11.50 (s, 1H), 8.66 (s, 1H), 27.40-7.46 (m, 3H), 7.22-7.33 (m, 9H), 6.89-6.91 (d, J = 8.0 Hz, 2H),5.89 (s, 1H), 4.71-4.73 (m, 1H), 4.59-4.62 (m, 1H), 4.50-4.56 (m, 3H),4.26-4.29 (m, 1H), 4.06-4.09 (m, 1), 3.99-4.02 (m, 1H), 3.88-3.96 (m,5H), 3.49-3.52 (m, 2H), 3.41-3.45 (m, 2H), 3.27-3.30 (m, 2), 3.09-3.13(m, 3H), 2.49 (s, 3H), 2.39-2.44 (m, 7H), 2.15 (s, 3H), 2.05-2.08 (m,1H), 1.76-1.80 (m, 2H), 1.63-1.69 (m, 6H), 1.51-1.55 (m, 2H), 0.96 (s,9H), 0.87-0.90 (t, J = 4.0 Hz, 3H). 47 B ¹HNMR (400 MHz, CDCl3): δ 11.50(br, 1H), 8.59 (s, 1H), 7.48-7.51 (m, 1H), 7.34 (d, J = 8.0 Hz, 2H),7.11-7.25 (m, 11H), 5.82 (s, 1H), 4.63 (t, J = 6.4 Hz, 1H), 4.42-4.52(m, 5H), 4.13-4.18 (m, 1H), 3.92-3.93 (m, 1H), 3.85-3.88 (m, 4H),3.50-3.60 (m, 5H), 3.37-3.41 (m, 3H), 3.21-3.28 (m, 2H), 2.95-3.05 (m,3H), 2.62 (t, J = 7.2 Hz, 2H), 2.29-2.41 (m, 10H), 2.08 (s, 3H),1.82-1.84 (m, 3H), 1.63-1.75 (m, 4H), 0.89 (s, 9H), 0.81 (t, J = 6.8 Hz,3H). 48 A ¹H NMR (400 MHz, CDCl₃): δ 11.03 (br, 1H), 8.68 (s, 1H), 27.43 (d, J = 8.0 Hz, 2H), 7.22-7.35 (m, 8H), 6.92 (d, J = 8.0 Hz, 2H),5.92 (s, 1H), 4.51-4.69 (m, 5H), 4.27-4.41 (m, 2H), 4.06-4.14 (m, 3H),3.79-3.95 (m, 4H), 3.52-3.58 (m, 7H), 3.31 (br, 3H), 3.01-3.08 (m, 3H),2.61 (m, 3H), 2.51 (s, 3H), 2.42 (m, 3H), 2.37 (s, 3H), 2.00-2.03 (m,3H), 1.84-1.87 (m, 2H), 0.95 (s, 9H), 0.84-0.89 (m, 3H). 49 B ¹H NMR(400 MHz, MeOD): δ 8.85 (s, 1H), 8.38-8.40 (m, 1H), 8 8.27 (s, 1H), 7.77(d, J = 8.0 Hz, 1H), 7.38-7.76 (m, 7H), 7.25 (s, 1H), 6.97-7.03 (m, 4H),6.08 (s, 1H), 4.39-4.63 (m, 10H), 4.06-4.15 (m, 4H), 3.79-3.98 (m, 6H),3.60-3.63 (m, 2H), 3.34-3.37 (m, 2H), 3.04-3.15 (m, 3H), 2.47 (m, 3H),2.39-2.44 (m, 1H), 2.38 (s, 3H), 2.30 (s, 3H), 2.22 (s, 3H), 2.15-2.19(m, 1H), 2.03-2.11 (m, 1H), 1.85-1.92 (m, 2H), 1.61-1.75 (m, 8H), 1.02(d, J = 8.0 Hz, 3H), 0.86-0.89 (m, 3H), 0.81 (d, J = 8.0 Hz, 3H). 50 A1H NMR (400 MHz, MeOD) δ 8.86 (s, 1H), 7.54 (d, J = 4.8 Hz, 8 1H),7.43-7.46 (m, 2H), 7.39-7.41 (m, 5H), 7.25 (s, 1H), 7.04-7.07 (m, 2H),6.92 (d, J = 8.8 Hz, 2H), 6.09 (s, 1H), 4.80 (m, 2H), 4.43-4.57 (m, 8H),4.24 (d, J = 2.8 Hz, 2H), 3.85-3.95 (m, 8H), 3.62 (t, J = 6.8 Hz, 2H),3.35-3.36 (m, 1H), 3.12-3.14 (m, 3H), 2.49 (s, 3H), 2.46-2.48 (m, 1H),2.38 (s, 3H), 2.31 (s, 3H), 2.23 (s, 3H), 2.05-2.22 (m, 2H), 1.67-1.76(m, 10H), 1.03 (d, J = 6.4 Hz, 3H), 0.88 (t, J = 6.8 Hz, 3H), 0.80 (d, J= 6.4 Hz, 3H) 51 B ¹H NMR (400 MHz, MeOD): δ 8.74 (s, 1H), 7.67 (d, J =8.0 Hz, 8 1H), 7.28-7.55 (m, 7H), 7.15 (s, 1H), 6.82 (m, 4H), 5.98 (s,1H), 4.30-4.53 (m, 10H), 3.97 (t, J = 6.4 Hz, 4H), 3.80 (m, 4H), 3.54(t, J = 6.0 Hz, 2H), 3.47 (t, J = 6.0 Hz, 2H), 3.25 (m, 1H), 3.04 (m,6H), 2.36 (s, 3H), 2.28 (s, 3H), 2.21 (s, 3H), 2.12 (s, 3H), 1.45-2.10(m, 16H), 0.92 (d, J = 6.4 Hz, 3H), 0.78 (t, J = 7.2 Hz, 3H), 0.70 (d, J= 6.8 Hz, 3H). 52 B ¹H NMR (400 MHz, CDCl₃): δ 8.75 (s, 1H), 7.78-7.79(m, 1H), 8 7.52-7.62 (m, 1H), 7.39-7.41 (m, 4H), 7.25-7.33 (m, 9H), 6.92(m, 1H), 6.87-6.89 (m, 3H), 5.95 (s, 1H), 4.45-4.78 (m, 11H), 4.37-4.41(m, 2H), 3.94-4.16 (m, 4H), 3.66-3.68 (m, 3H), 3.54-3.55 (m, 2H),3.32-3.38 (m, 2H), 3.01-3.21 (m, 3H), 2.54 (s, 3H), 2.36-2.42 (m, 10H),2.13-2.23 (m, 9H), 1.98-2.04 (m, 2H), 1.71-1.86 (m, 12H), 0.86-0.93 (m,9H) 53 B ¹H NMR (400 MHz, CDCl₃) δ 10.79-11.15 (m, 1H), 8.68 (s, 8 1H),7.70 (d, J = 6.2 Hz, 1H), 7.47 (d, J = 6.8 Hz, 1H), 7.38 (s, 4H), 7.32(d, J = 8.0 Hz, 1H), 7.15 (s, 1H), 6.98 (d, J = 7.7 Hz, 1H), 6.83-6.93(m, 3H), 5.94 (s, 1H), 4.67-4.85 (m, 2H), 4.51 (s, 4H), 4.39 (s, 3H),4.19 (s, 2H), 3.79-4.04 (m, 6H), 3.64 (d, J = 6.0 Hz, 3H), 3.31 (s, 2H),3.04 (d, J = 29.7 Hz, 3H), 2.53 (s, 3H), 2.41 (s, 3H), 2.36 (s, 3H),2.27 (s, 3H), 1.88 (d, J = 5.8 Hz, 3H), 1.81 (d, J = 6.7 Hz, 3H), 1.70(s, 6H), 0.72-0.96 (m, 9H). 54 B ¹HNMR (400 MHz, MeOD): δ 8.83 (s, 1H),8.35 (t, J = 5.6 Hz, 8 1H), 8.26 (m, 1H), 7.75 (d, J = 7.6 Hz, 1H),7.37-7.58 (m, 8H), 7.24 (s, 1H), 7.00-7.02 (m, 2H), 6.92 (d, J = 8.8 Hz,2H), 6.07 (s, 1H), 4.42-4.61 (m, 9H), 4.17-4.20 (m, 6H), 3.84-3.98 (m,6H), 3.63-3.74 (m, 6H), 2.37-2.45 (m, 6H), 2.30 (s, 3H), 2.01-2.21 (m,4H), 1.97-2.07 (m, 5H), 1.56-1.74 (m, 4H), 1.22-1.28 (m, 2H), 1.02 (d, J= 6.4 Hz, 3H), 0.86 (t, J = 13.6 Hz, 3H), 0.79 (d, J = 6.4 Hz, 3H). 55 B¹H NMR (400 MHz, CDCl3): δ 11.027 (s, 1H), 8.678 (s, 1H), 8 7.72 (d, J =7.6, 1H), 7.49-7.51 (m, 1H), 7.40 (d, J = 7.2, 4H), 7.19-7.32 (m, 6H),6.97 (d, J = 7.6, 1H), 6.88-6.90 (m, 3H), 5.91 (s, 1H), 4.73-4.80 (m,2H), 4.34-4.57 (m, 8H), 4.18-4.21 (m, 2H), 3.92-3.98 (m, 6H), 3.73-3.74(m, 2H), 3.62-3.65 (m, 3H), 3.51 (t, J = 6.4, 2H), 3.31 (t, J = 10.8,2H), 3.01-3.09 (m, 3H), 2.52 (s, 3H), 2.36-2.40 (m, 6H), 2.23-2.28 (m,3H), 1.93-1.98 (m, 1H), 1.79-1.84 (m, 3H), 1.71-1.76 (m, 7H), 0.85-0.94(m, 10H). 56 B ¹H NMR (400 MHz, MeOD) δ 8.84-8.87 (m, 1H), 7.76-7.80 (m,8 1H), 7.46-7.64 (m, 4H), 7.41-7.45 (m, 2H), 7.38-7.40 (m, 1H),7.25-7.28 (m, 1H), 7.01-7.07 (m, 2H), 6.90-6.95 (m, 2H), 6.06-6.14 (m,2H), 4.85-4.88 (m, 1H), 4.62-4.65 (m, 1H), 4.57-4.60 (m, 1H), 4.52-4.56(m, 1H), 4.43-4.52 (m, 5H), 4.23-4.29 (m, 2H), 4.07-4.14 (m, 2H),3.85-4.00 (m, 6H), 3.78-3.83 (m, 2H), 3.09-3.18 (m, 3H), 2.48 (s, 3H),2.40 (s, 3H), 2.33 (s, 2H), 2.24 (s, 3H), 2.12-2.22 (m, 3H), 2.02-2.12(m, 4H), 1.70-1.81 (m, 3H), 1.57-1.70 (m, 4H), 1.28-1.39 (m, 6H),1.01-1.05 (m, 2H), 0.87-0.95 (m, 4H), 0.78-0.85 (m, 3H) 57 B ¹H NMR (400MHz, MeOD): δ 7.82 (s, 1H), 7.71 (d, J = 8.3 Hz, 10 2H), 7.60 (d, J =7.9 Hz, 2H), 7.39 (d, J = 2.0 Hz, 1H), 7.29 (dd, J = 8.3, 2.1 Hz, 1H),6.98 (d, J = 8.7 Hz, 2H), 6.12 (s, 1H), 5.07 (dd, J = 12.7, 5.5 Hz, 1H),4.50 (s, 2H), 4.31-4.37 (m, 2H), 4.15-4.21 (m, 2H), 3.89-4.12 (m, 8H),3.78 (s, 3H), 3.43 (d, J = 39.1 Hz, 3H), 2.57-2.94 (m, 6H), 2.42 (s,3H), 2.40 (s, 3H), 2.24 (s, 3H), 2.18 (dd, J = 16.0, 10.1 Hz, 1H),2.00-2.12 (m, 2H), 1.05 (s, 3H). 58 A ¹H NMR (400 MHz, CDCl₃): δ 10.52(s, 1H), 10.15-10.31 (m, 10 2H), 7.67 (d, J = 8.3 Hz, 1H), 7.33-7.43 (m,3H), 7.22 (d, J = 8.1 Hz, 2H), 7.15 (d, J = 8.3 Hz, 1H), 6.81 (d, J =8.5 Hz, 2H), 5.94 (s, 1H), 4.87 (d, J = 6.9 Hz, 1H), 4.55 (s, 2H), 4.25(t, J = 6.0 Hz, 2H), 4.09 (d, J = 4.6 Hz, 2H), 3.95 (d, J = 11.7 Hz,2H), 3.83 (d, J = 4.2 Hz, 2H), 3.75 (t, J = 5.5 Hz, 2H), 3.33 (t, J =11.0 Hz, 3H), 3.09 (d, J = 7.3 Hz, 2H), 3.01 (s, 1H), 2.64-2.88 (m, 4H),2.42 (s, 3H), 2.32 (s, 3H), 2.22 (s, 3H), 2.10 (dd, J = 17.3, 11.5 Hz,4H), 1.63-1.77 (m, 4H), 0.90 (t, J = 6.9 Hz, 3H). 59 B 1H NMR (400 MHz,CDCl3): δ: 8.66 (s, 1H), 7.40-7.42 (m, 4H), 2 7.33-7.38 (m, 6H),7.21-7.23 (m, 2H), 6.89 (d, J = 8.4 Hz, 1H), 5.92 (s, 1H), 5.02-5.10 (m,1H), 4.83 (t, J = 8.0 Hz, 1H), 4.73 (d, J = 8.8 Hz, 1H), 4.49-4.56 (m,3H), 4.03-4.11 (m, 2H), 3.85-3.97 (m, 4H), 3.57-3.69 (m, 8H), 3.46 (s,2H), 3.31 (s, 2H), 3.08 (s, 7H), 2.50 (s, 3H), 2.43 (s, 3H), 2.37 (s,3H), 2.20 (s, 3H), 2.02 (s, 2H), 1.65-1.78 (m, 8H), 1.04 (s, 9H), 0.88(t, J = 6.4 Hz, 3H). 60 A ¹HNMR (400 MHz, CDCl₃): δ 9.69-9.80 (m, 2H),7.75 (d, J = 8.4 Hz, 10 1H), 7.42 (d, J = 8.8 Hz, 2H), 7.32 (s, 1H),7.14-7.19 (m, 3H), 6.82 (d, J = 8.8 Hz, 2H), 5.93 (s, 1H), 4.91-4.94 (m,1H), 4.20-4.30 (m, 2H), 4.03-4.10 (m, 2H), 3.96 (d, J = 11.6 Hz, 2H),3.35-3.23 (m, 2H), 3.05-3.15 (m, 2H), 3.01 (s, 1H), 2.86-3.00 (m, 3H),2.41 (s, 3H), 2.33 (s, 3H), 2.30 (s, 4H), 2.12-2.15 (m, 1H), 2.02-2.06(m, 5H), 1.66-1.71 (m, 5H), 0.88-0.91 (m, 3H). 61 B 1HNMR (400 MHz,MeOD): δ 7.67-7.69 (d, J = 8 Hz, 1H), 11 7.48-7.50 (d, J = 8 Hz, 2H),7.37-7.40 (d, J = 12 Hz, 1H), 7.23-7.26 (m, 2H), 6.97-7.00 (d, J = 12Hz, 2H), 611 (s, 1H), 5.04-5.07 (m, 1H), 4.48 (s, 2H), 4.10-4.12 (t, J =8 Hz, 2H), 3.90-3.93 (m, 2H), 3.49 (s, 4H), 3.38-3.49 (m, 2H), 3.13-3.15(m, 3H), 2.82-2.85 (m, 1H), 2.65-2.69 (m, 8H), 2.39 (s, 3H), 2.30 (s,3H), 2.23 (s, 3H), 2.03-2.07 (m, 4H), 1.73-1.76 (m, 2H), 1.62-1.64 (m,2H), 0.90-0.92 (t, J = 8 Hz, 3H). 62 B ¹H NMR (400 MHz, CDCl₃): δ10.15-10.24 (m, 1H), 10 7.65-7.71 (m, 1H), 7.40 (d, J = 8.7 Hz, 2H),7.32 (s, 1H), 7.22 (s, 1H), 7.09-7.17 (m, 2H), 6.84 (d, J = 8.6 Hz, 2H),5.96 (s, 1H), 4.85-4.91 (m, 1H), 4.55 (d, J = 6.0 Hz, 2H), 4.18 (s, 2H),4.03 (s, 2H), 3.92-3.98 (m, 2H), 3.63 (d, J = 5.7 Hz, 3H), 3.27-3.37 (m,2H), 3.08 (s, 2H), 3.04-2.96 (m, 1H), 2.68-2.89 (m, 4H), 2.43 (s, 3H),2.31 (s, 3H), 2.24 (s, 3H), 2.07 (d, J = 6.7 Hz, 4H), 1.71 (s, 4H), 0.90(t, J = 6.9 Hz, 3H). 63 B 8 64 B 1H NMR (400 MHz, CDCl3) δ 10.87-11.15(m, 1H), 8.70 (s, 8 1H), 7.63 (d, J = 7.6 Hz, 1H), 7.46 (d, J = 8.5 Hz,3H), 7.36 (t, J = 8.5 Hz, 3H), 7.30 (d, J = 9.7 Hz, 3H), 7.01 (d, J =8.7 Hz, 3H), 6.97 (s, 1H), 6.72 (s, 1H), 5.98 (s, 1H), 4.76-4.86 (m,2H), 4.74 (s, 1H), 4.28-4.57 (m, 12H), 4.15 (s, 1H), 3.95 (d, J = 10.5Hz, 2H), 3.50 (d, J = 7.8 Hz, 1H), 3.32 (s, 3H), 3.10 (d, J = 6.8 Hz,2H), 3.01 (s, 1H), 2.56 (s, 3H), 2.42 (s, 3H), 2.40 (d, J = 4.4 Hz, 3H),2.38 (s, 3H), 0.97 (d, J = 6.4 Hz, 3H), 0.91 (t, J = 6.9 Hz, 3H), 0.83(d, J = 6.6 Hz, 3H). 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 8182 83 84 85 86 87 88 A 1H NMR (400 MHz, MeOD) δ 8.87 (s, 1H), 8.55 (d, J= 7.3 Hz, 2 1H), 8.30 (s, 1H), 7.85 (d, J = 9.2 Hz, 1H), 7.48 (d, J =8.0 Hz, 2H), 7.34-7.46 (m, 6H), 7.23-7.32 (m, 3H), 6.11 (s, 1H),4.96-5.05 (m, 2H), 4.63 (d, J = 8.9 Hz, 1H), 4.57 (t, J = 8.4 Hz, 2H),4.49 (d, J = 4.7 Hz, 2H), 4.43 (s, 1H), 3.90 (t, J = 12.4 Hz, 3H),3.71-3.78 (m, 1H), 3.44 (dd, J = 9.9, 6.1 Hz, 4H), 3.37 (d, J = 11.5 Hz,2H), 3.13 (dd, J = 16.2, 9.6 Hz, 4H), 2.72 (t, J = 7.4 Hz, 2H), 2.47 (s,3H), 2.39 (s, 3H), 2.32 (s, 4H), 2.24 (s, 3H), 2.17 (d, J = 8.6 Hz, 1H),1.84-1.99 (m, 4H), 1.54-1.81 (m, 10H), 1.48 (t, J = 8.2 Hz, 3H), 1.04(s, 9H), 0.90 (t, J = 6.9 Hz, 3H 89 A 1H NMR (400 MHz, MeOD): δ 8.89 (s,1H), 8.56 (d, J = 9.6 Hz, 2 1H), 7.69 (d, J = 9.6 Hz, 1H), 7.49-7.53 (m,3H), 7.31-7.44 (m, 7H), 6.12 (s, 1H), 4.72 (d, J = 9.6 Hz, 1H), 4.59 (t,J = 8 Hz, 1H), 4.51 (s, 3H), 4.46 (s, 2H), 4.08 (d, J = 1.6 Hz, 2H),3.86-3.94 (m, 3H), 3.75-3.79 (m, 3H), 3.67-3.68 (m, 2H), 3.54-3.57 (m,2H), 3.19 (s, 3H), 2.77 (d, J = 7.6 Hz, 2H), 2.48 (s, 3H), 2.40 (s, 3H),2.35 (s, 3H), 2.25 (s, 3H), 2.18-2.21 (m, 1H), 1.94-2.09 (m, 3H),1.75-1.78 (m, 2H), 1.57-1.69 (m, 3H), 1.45 (d, J = 6.8 Hz, 3H), 1.07 (s,9H), 0.92 (t, J = 6.8 Hz, 3H). 90 B 1H NMR (400 MHz, MeOD) δ 8.86 (s,1H), 8.35 (d, J = 48.7 Hz, 8 1H), 7.74 (d, J = 7.5 Hz, 1H), 7.56-7.62(m, 1H), 7.52 (d, J = 7.5 Hz, 1H), 7.39-7.50 (m, 4H), 7.37 (s, 1H), 7.25(s, 1H), 7.02 (dd, J = 15.5, 6.6 Hz, 4H), 6.09 (s, 1H), 4.81 (d, J =10.9 Hz, 1H), 4.39-4.63 (m, 8H), 4.26 (t, J = 15.2 Hz, 4H), 3.80-4.01(m, 4H), 3.36 (d, J = 10.9 Hz, 2H), 3.01-3.17 (m, 3H), 2.46 (d, J = 10.4Hz, 3H), 2.38 (s, 3H), 2.31 (s, 3H), 2.23 (s, 3H), 2.19-2.03 (m, 2H),1.74 (d, J = 11.5 Hz, 2H), 1.62 (d, J = 11.8 Hz, 2H), 1.01 (d, J = 6.5Hz, 3H), 0.88 (t, J = 6.9 Hz, 3H), 0.79 (d, J = 6.5 Hz, 3H). 91 A 1H NMR(400 MHz, MeOD) δ 7.68 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 8.4 Hz, 11 2H),7.41 (s, 1H), 7.37 (s, 1H), 7.24-7.27 (m, 2H), 7.02 (d, J = 8.4 Hz, 2H),6.11 (s, 1H), 5.04-5.08 (m, 1H), 4.48 (s, 2H), 4.22 (t, J = 4.8 Hz, 2H),3.92 (d, J = 10.0 Hz, 2H), 3.35 (s, 4H), 3.30-3.32 (m, 2H), 3.00-3.18(m, 3H), 2.72-2.91 (m, 9H), 2.39 (s, 3H), 2.31 (s, 3H), 2.24 (s, 3H),2.10-2.13 (m, 1H), 1.74-1.77 (m, 2H), 1.62-1.65 (m, 2H), 0.88 (t, J =6.8 Hz, 3H). 92 B 1HNMR (400 MHz, MeOD): δ 7.68-7.70 (d, J = 8 Hz, 1H),11 7.50-7.52 (d, J = 8 Hz, 2H), 7.42 (s, 1H), 7.37 (s, 1H), 7.29 (s,1H), 7.23-7.25 (d, J = 8 Hz, 1H), 6.99-7.01 (d, J = 8 Hz, 2H), 613 (s,1H), 5.07-5.10 (m, 1H), 4.50 (s, 2H), 4.09-4.10 (t, J = 4 Hz, 2H),3.92-3.94 (m, 2H), 3.49 (s, 4H), 3.37-3.40 (m, 2H), 3.07-3.15 (m, 3H),2.78-2.84 (m, 1H), 2.68-2.74 (m, 6H), 2.52-2.54 (m, 2H), 2.41 (s, 3H),2.32 (s, 3H), 2.26 (s, 3H), 2.07-2.12 (m, 3H), 1.78-1.87 (m, 6H),1.63-1.75 (m, 2H), 0.90-0.92 (t, J = 8 Hz, 3H). 93 A 1H NMR (400 MHz,CDCl3): δ 11.42 (s, 1H), 8.66 (s, 1H), 2 7.42 (d, J = 8.4 Hz, 1H),7.39-7.33 (m, 6H), 7.29-7.22 (m, 4H), 6.91 (d, J = 8.4 Hz, 2H), 5.90 (s,1H), 5.08-5.02 (m, 1H), 4.78-4.73 (m, 1H), 4.62-4.50 (m, 4H), 4.08-3.93(m, 7H), 3.78 (s, 1H), 3.68-3.61 (m, 3H), 3.48 (s, 1H), 3.31-3.30 (m,2H), 3.08-3.07 (m, 3H), 2.51 (s, 4H), 2.40 (s, 3H), 2.34 (s, 3H), 2.15(s, 3H), 2.08-2.01 (m, 1H), 1.88-1.82 (m, 7H), 1.76 (s, 3H), 1.45 (d, J= 6.8 Hz, 3H), 1.06 (s, 9H), 0.88 (t, J = 6.8 Hz, 3H). 94 A 1H NMR (400MHz, MeOD) δ 8.87 (s, 1H), 8.53-8.61 (m, 1H), 2 8.25-8.31 (m, 1H),7.53-7.57 (m, 1H), 7.49 (d, J = 8.6 Hz, 2H), 7.41 (t, J = 8.2 Hz, 5H),7.28 (s, 1H), 6.98 (d, J = 8.6 Hz, 2H), 6.10 (s, 1H), 4.94-5.04 (m, 2H),4.66-4.73 (m, 1H), 4.52-4.62 (m, 2H), 4.48 (s, 2H), 4.41-4.46 (m, 1H),4.04 (d, J = 6.2 Hz, 2H), 3.99 (d, J = 7.2 Hz, 2H), 3.81-3.95 (m, 3H),3.71-3.78 (m, 1H), 3.61 (t, J = 6.0 Hz, 2H), 3.35 (s, 2H), 3.14 (d, J =6.9 Hz, 4H), 2.47 (s, 3H), 2.38 (s, 3H), 2.31 (s, 3H), 2.23 (s, 3H),2.17-2.21 (m, 1H), 1.90-1.99 (m, 2H), 1.81-1.90 (m, 2H), 1.73 (s, 4H),1.63 (d, J = 7.0 Hz, 5H), 1.47 (d, J = 6.9 Hz, 3H), 1.04 (s, 9H), 0.89(t, J = 6.8 Hz, 3H). 95 A 1H NMR (400 MHz, MeOD): 8.86 (s, 1H), 7.51 (d,J = 8.0 Hz, 2 2H), 7.37-7.46 (m, 5H), 7.27 (s, 1H), 7.02 (d, J = 8.4 Hz,2H), 6.12 (s, 1H), 4.72 (d, J = 9.6 Hz, 1H), 4.55-4.60 (m, 1H), 4.61 (s,3H), 4.08 (s, 2H), 3.85-3.94 (m, 3H), 3.75-3.78 (m, 3H), 3.66-3.68 (m,2H), 3.54-3.57 (m, 2H), 3.19 (s, 3H), 2.75-2.77 (m, 2H), 2.48 (s, 3H),2.40 (s, 3H), 2.35 (s, 3H), 2.25 (s, 3H), 2.18-2.21 (m, 1H), 1.94-2.09(m, 3H), 1.75-1.78 (m, 2H), 1.57-1.69 (m, 3H), 1.45 (d, J = 6.8 Hz, 3H),1.07 (s, 9H), 0.92 (t, J = 6.8 Hz, 3H). 96 B 1HNMR (400 MHz, MeOD): δ8.82 (s, 1H), 7.44-7.46 (m, 4H), 2 7.38-7.39 (m, 3H), 7.25 (s, 1H), 6.94(d, J = 8.8 Hz, 2H), 6.10 (s, 1H), 4.98-5.00 (m, 1H), 4.53-4.59 (m, 2H),4.46-4.48 (m, 3H), 4.00-4.09 (m, 4), 3.89-3.92 (m, 3H), 3.65-3.77 (m,7H), 3.30-3.33 (m, 2), 3.12-3.14 (m, 3), 2.43 (s, 3H), 2.39 (m, 3H),2.30 (s, 3H), 2.20-2.23 (m, 4H), 2.05-2.08 (m, 1H), 1.72-1.75 (m, 2H),1.61-1.63 (m, 2H), 1.42 (d, J = 6.8 Hz, 3H), 1.03 (s, 9H), 0.90 (t, J =6.8 Hz, 3H). 97 B 1H NMR (400 MHz, CDCl3) δ 0.78-0.90 (3H, m), 0.96-1.06(3H, 12 m), 1.34-1.35 (3H, m), 1.67-1.69 (6H, m), 1.99-2.10 (1H, m),2.15-2.18 (3H, m), 2.20-2.33 (6H, m), 2.40 (3H, m), 2.45-2.55 (4H, m),2.96-3.11 (3H, m), 3.28-3.34 (2H, m), 3.64-3.81 (2H, m), 3.90-3.95 (2H,m), 4.17-4.40 (5H, m), 4.50-4.80 (6H, m), 4.94-5.24 (1H, m), 5.88-5.92(1H, m), 6.92-7.00 (2H, m), 7.06-7.24 (8H, m), 7.28-7.52 (7H, m),8.67-8.70 (1H, m), 10.48-10.52 (1H, m). 98 B 1H NMR (400 MHz, CDCl3) δ0.84-0.88 (3H, m), 1.04-1.06 (3H, 12 m), 1.43-1.46 (3H, m), 1.63-1.69(6H, m), 2.01-2.30 (7H, m), 2.33-2.39 (6H, m), 2.52 (3H, m), 2.95-3.11(4H, m), 3.23-3.34 (2H, m), 3.65-3.76 (1H, m), 3.90-3.96 (2H, m),4.12-4.83 (12H, m), 5.03-5.11 (1H, m), 5.87-5.89 (1H, m), 6.85-6.95 (2H,m), 7.08-7.24 (4H, m), 7.29-7.62 (11H, m), 8.67 (1H, m), 10.91-10.92(1H, m). 99 A 1H NMR (400 MHz, DMSO-d6) δ 0.68-0.73 (3H, m), 120.81-0.84 (3H, m), 0.95-0.98 (4H, m), 1.34-1.38 (3H, m), 1.51-1.53 (2H,m), 1.64-1.67 (2H, m), 1.75-1.79 (1H, m), 2.10 (3H, s), 2.20 (3H, s),2.24 (3H, s), 2.45 (3H, s), 3.08-3.11 (2H, m), 3.22-3.27 (3H, m),3.65-3.73 (2H, m), 3.80-3.83 (5H, m), 4.23-4.25 (2H, m), 4.28-4.29 (2H,m), 4.33-4.38 (2H, m), 4.44-4.50 (2H, m), 4.56 (2H, s), 4.67-4.70 (1H,m), 4.90-4.94 (1H, m), 5.08-5.09 (1H, m), 5.85 (1H, s), 7.20-7.22 (3H,m), 7.35-7.37 (2H, m), 7.40-7.46 (5H, m), 7.51-7.53 (2H, m), 7.60-7.62(2H, m), 8.22 (1H, t, J = 4.8 Hz), 8.43 (1H, d, J = 7.2 Hz), 8.99 (1H,s), 11.4 (1H, d, J = 4.8 Hz). 100 A 1H NMR (400 MHz, CDCl3) δ 0.94 (3H,d, J = 6.8 Hz), 12 1.05 (3H, d, J = 6.8 Hz), 1.46 (3H, d, J = 6.8 Hz),1.71 (3H, m), 2.01 (3H, m), 2.22 (3H, s), 2.34 (3H, s), 2.41 (3H, s),2.49 (1H, d, J = 5.6 Hz), 2.53 (3H, s), 2.99-3.11 (3H, m), 3.32 (2H, m),3.65 (1H, dd, J = 4.0, 8.0 Hz), 3.96 (2H, m), 4.35-4.41 (6H, m),4.46-4.55 (4H, m), 4.70 (2H, m), 4.79 (1H, d, J = 11.2 Hz), 5.09 (1H,m), 5.35 (2H, t, J = 4.6 Hz), 5.92 (1H, s), 6.95-7.00 (2H, m), 7.06 (1H,t, J = 4.8 Hz), 7.17-7.20 (2H, m), 7.32-7.43 (10H, m), 7.52-7.53 (2 H,m), 8.67 (1H, s). 101 B 1H NMR (400 MHz, CDCl3) δ 0.86-0.91 (3H, m),1.06 (3H, d, J = 6.4 Hz), 12 1.50 (3H, J = 9.6 Hz), 1.67-1.70 (6H, m),2.00-2.05 (4H, brs), 2.19 (3H, s), 2.29-2.51 (8H, m), 2.53 (3H, s),3.06-3.11 (3H, m), 3.32 (3H, t, J = 10.8 Hz), 3.74-3.80 (2H, m),3.93-4.11 (7H, m), 4.28-4.68 (7H, m), 4.78-4.85 (1H, m), 4.97-5.00 (1H,m), 5.91 (1H, s), 6.88-6.90 (2H, m), 7.01-7.23 (6H, m), 7.26-7.46 (7H,m), 8.66 (1H, s), 10.51-10.58 (1H, brs). 102 B 1H NMR (400 MHz, CDCl3) δ0.91-0.93 (3H, m), 1.05 (3H, J = 6.4 Hz), 12 1.45 (3H, J = 6.8 Hz),1.68-1.70 (5H, m), 1.99-2.03 (5H, brs), 2.20 (3H, s), 2.34-2.53 (12H,m), 3.00-3.28 (4H, m), 3.28-3.34 (2H, m), 3.67-3.69 (1H, m), 3.93-3.96(2H, d, J = 11.2 Hz), 4.06-4.07 (4H, m), 4.34-4.53 (5H, m), 4.65-4.68(2H, m), 4.78 (1H, d, J = 11.2 Hz), 5.06-5.11 (1H, m), 5.90 (1H, s),6.90 (2H, d, J = 8.4 Hz), 7.07-7.17 (4H, m), 7.29-7.40 (8H, m), 7.59(1H, d, J = 7.6 Hz), 8.67 (1H, s), 10.80-10.86 (1H, brs). 103 B 12 104 A1H NMR (400 MHz, CDCl3) δ 0.86-0.88 (6 H, m), 13 1.01-1.03 (3H, m),1.35-1.42 (4H, m), 1.63-1.69 (5H, brs), 1.82-1.84 (4H, brs), 1.95-1.98(1H, m), 2.12-2.19 (3H, m), 2.34 (3H, d, J = 5.6 Hz), 2.40-2.41 (4H, m),2.52 (3H, d, J = 3.2 Hz), 2.88 (1H, s), 2.96 (1H, s), 2.97-3.11 (3H, m),3.28-3.34 (2H, m), 3.44-3.66 (3H, m), 3.70 (1H, s), 3.78-4.03 (5H, m),4.18-4.23 (2H, m), 4.36-4.50 (1H, m), 4.56-4.79 (3H, m), 4.93-5.07 (1H,m), 5.81 (1H, d, J = 9.6 Hz), 5.91 (1H, d, J = 14.4 Hz), 6.90 (2H, d, J= 8.0 Hz), 7.06-7.21 (2H, m), 7.27-7.41 (8H, m), 7.79-8.01 (1H, m), 8.67(1H, d, J = 2.8 Hz). 105 A 1H NMR (400 MHz, CDCl3) δ 0.88-0.90 (3H, m),0.97-1.01 (3H, 13 m), 1.26-1.42 (6H, m), 1.68-1.70 (5H, m), 1.93-1.99(1H, m), 2.12-2.18 (3 H, m), 2.34-2.36 (3H, m), 2.40-2.42 (3H, m), 2.52(3H, m), 2.96-3.59 (9H, m), 3.77-3.96 (7H, m), 4.15-4.19 (2H, m),4.32-4.80 (6H, m), 4.93-5.06 (1H, m), 5.74-5.95 (2H, m), 6.91-6.94 (2H,m), 7.10-7.24 (2H, m), 7.28-7.42 (8H, m), 7.48-7.89 (1H, m), 8.67 (1H,m). 106 A 1H NMR (400 MHz, CDCl3) δ 0.86-0.92 (6 H, m), 13 1.02-1.05(3H, m), 1.33-1.36 (3H, m), 1.50-1.52 (4H, m), 1.70-1.84 (8H, m),1.99-2.02 (1H, m), 2.17-2.28 (3H, m), 2.33-2.36 (3H, m), 2.41-2.42 (3H,m), 2.52-2.53 (3H, m), 2.98-3.09 (3H, m), 3.29-3.37 (2H, m), 3.46-3.88(4H, m), 3.94-4.05 (4H, m), 4.19-4.25 (3H, m), 4.42-4.81 (4H, m),4.93-5.07 (1H, m), 5.34-5.36 (1H, m), 5.81-5.82 (1H, m), 5.91-5.96 (1H,m), 6.91-6.93 (3H, m), 7.12-7.19 (1H, m), 7.29-7.42 (8H, m), 7.58-8.13(1H, m), 8.67-8.68 (1H, m). 107 A 1H NMR (400 MHz, CDCl3) δ 0.89-0.91(3H, m), 1.01-1.04 (3H, 13 m), 1.26-1.43 (6H, m), 1.66 (6H, m),1.95-1.98 (5H, m), 2.13-2.19 (3H, m), 2.33-2.35 (3H, m), 2.40-2.41 (3H,m), 2.51-2.52 (3H, m), 3.00-3.11 (4H, m), 3.29-3.34 (2H, m), 3.51-3.64(3H, m), 3.93-4.05 (4H, m), 4.27 (2H, m), 4.32-4.50 (1H, m), 4.57-4.80(3H, m), 4.92-5.08 (1H, m), 5.80-5.94 (2H, m), 6.89-6.91 (2H, m),7.12-7.18 (2H, m), 7.28-7.44 (8H, m), 7.53-7.83 (1H, m), 8.67 (1H, m).108 B 1H NMR (400 MHz, CDCl3) δ 0.86-0.91 (3H, m), 0.97 (3H, d, J = 6.8Hz), 12 1.01 (3H, d, J = 6.4 Hz), 1.35 (3H, d, J = 6.8 Hz), 1.68-1.71(4H, m), 1.99-2.03 (2H, m), 2.27 (3H, s), 2.36 (3H, s), 2.42 (3H, s),2.52 (3H, s), 2.98-3.12 (3H, m), 3.28-3.36 (2H, m), 3.72-3.80 (2H, m),3.81-3.92 (2H, m), 3.92-3.950 (2H, m), 4.18-4.29 (3H, m), 4.36 (1H, d, J= 8.8 Hz), 4.58-4.61 (1H, m), 4.69 (2H, s), 4.71-4.75 (1 H, m),4.89-4.93 (1H, dd, J = 4.8, 8.0 Hz), 5.01-5.04 (1H, t, J = 7.2 Hz), 5.30(3H, s), 5.35 (1H, t, J = 4.6 Hz), 5.94 (1H, s), 6.98 (2H, t, J = 7.0Hz), 7.17 (1H, s), 7.32-7.38 (7H, m), 7.41 (2H, J = 8.8 Hz), 7.49-7.52(2H, m), 7.96 (1H, s), 8.32 (1H, d, J = 7.2 Hz), 8.67 (1H, s). 109 A 1HNMR (400 MHz, CDCl3) δ 0.86-0.90 (3H, m), 0.98-0.99 (3H, 13 m),1.35-1.43 (3H, m), 1.70-1.73 (5H, m), 1.94-2.06 (3H, m), 2.08-2.16 (3H,m), 2.34-2.36 (3H, m), 2.39-2.41 (3H, m), 2.51-2.52 (3H, m), 2.98-3.37(6H, m), 3.43-3.81 (8H, m), 3.92-3.95 (2H, m), 4.11-4.15 (2H, m),4.29-4.32 (2H, m), 4.34-4.78 (4H, m), 4.90-5.08 (1H, m), 5.78-5.79 (1H,m), 5.89-5.93 (1H, m), 6.91-6.94 (2H, m), 7.17-7.25 (2H, m), 7.27-7.42(8H, m), 7.48-7.89 (1H, m), 8.67 (1H, m). 110 A 1H NMR (400 MHz, CDCl3)δ 0.84-0.90 (3H, m), 0.94-1.03 (6H, 13 m), 1.25 (3H, m), 1.30-1.36 (3H,m), 2.16-2.24 (3H, m), 2.34-2.42 (6H, m), 2.49-2.52 (3H, m), 2.91-3.10(8H, m), 3.24-3.56 (6H, m), 3.75-3.78 (4H, m), 3.93-3.96 (2H, m),4.29-4.79 (8H, m), 5.82-5.98 (2H, m), 7.00-7.17 (4H, m), 7.30-7.42 (9H,m), 8.65-8.68 (1H, m). 111 A 1H NMR (400 MHz, CDCl3) δ 0.81-0.83 (3H,m), 0.93-0.97 (6H, 13 m), 1.26-1.30 (5H, m), 1.82-1.89 (4H, m), 2.08(1H, s), 2.19 (2H, s), 2.25-2.27 (4H, m), 2.34-2.35 (4H, m), 2.45 (4H,d, J = 4.4 Hz), 2.63 (2H, brs), 2.91-3.04 (4H, m), 3.22-3.26 (2H, m),3.35-3.49 (5H, m), 3.66-3.70 (2H, m), 3.75-3.79 (1H, m), 3.86-3.89 (2H,m), 4.16-4.21 (1H, m), 4.24-4.30 (2H, m), 4.33-4.46 (1H, m), 4.52-4.55(1H, m), 4.64-4.72 (2H, m), 4.83-4.98 (1H, m), 5.78-5.89 (2H, m),6.93-6.94 (1H, m), 7.09-7.17 (3H, m), 7.21-7.33 (9H, m), 8.60 (1H, d, J= 3.6 Hz). 112 A 1H NMR (400 MHz, CDCl3) δ 0.79-0.91 (6 H, m), 130.94-1.02 (3H, m), 1.31-2.34 (3H, m), 1.65-1.69 (4H, m), 1.93-2.09 (3H,m), 2.15-2.24 (3H, m), 2.30-2.33 (3H, m), 2.41-2.42 (3H, m), 2.51-2.52(3H, m), 2.96-3.11 (3H, m), 3.25-3.36 (2H, m), 3.43-3.55 (3H, m),3.66-3.85 (6H, m), 3.89-3.95 (2H, m), 4.07-4.23 (3H, m), 4.28-4.45 (3H,m), 4.51-4.66 (2H, m), 4.74-4.81 (1H, m), 4.90-5.06 (1H, m), 5.70-5.82(1H, m), 5.90-5.97 (1H, m), 6.92-6.95 (2H, m), 7.00-7.24 (2H, m),7.27-7.43 (8H, m), 7.63-8.20 (1H, m), 8.66-8.67 (1H, m). 113 B 1HNMR(400 MHz, MeOD-d4): δ: δ: 7.66 (d, J = 8.4 Hz, 1H), 14 7.60-7.59 (m,2H), 7.46 (s, 3H), 7.33 (s, 2H), 7.22-7.19 (m, 1H), 6.12 (s, 1H),5.06-5.03 (m, 1H), 4.05-4.03 (m, 2H), 3.92 (d, J = 10.8 Hz, 3H), 3.84(s, 1H), 3.39-3.37 (m, 2H), 3.18-3.14 (m, 4H), 3.10-3.00 (m, 3H),2.89-2.69 (m, 9H), 2.50 (s, 3H), 2.40 (s, 3H), 2.35 (s, 3H), 2.25 (s,3H), 2.21-2.19 (m, 1H), 2.17-2.10 (m, 2H), 2.03-2.02 (m, 1H), 1.94-1.91(m, 3H), 1.77-1.74 (m, 2H), 1.68-1.60 (m, 3H), 0.90 (t, J = 6.8 Hz, 3H).114 A 1H NMR SL-ARV-LS-011E (400 MHz, CDCl3): δ: 8.60 (s, 1H), 27.07-7.49 (m, 15H), 5.85 (s, 1H), 4.96-5.06 (m, 1H), 4.49-4.63 (m, 2H),4.37-4.42 (m, 3H), 3.83-4.03 (m, 5H), 3.46-3.67 (m, 8H), 3.44 (s, 2H),3.41 (s, 3H), 3.24 (t, J = 10.9 Hz, 2H), 2.99-3.04 (m, 2H), 2.93 (d, J =4.7 Hz, 1H), 2.49-2.62 (m, 5H), 2.45 (s, 3H), 2.34 (s, 3H), 2.29 (s,3H), 2.12 (s, 3H), 1.80-1.97 (m, 4H), 1.53-1.57 (m, 3H), 1.40 (d, J =6.9 Hz, 3H), 0.96 (s, 9H), 0.82 (t, J = 6.9 Hz, 3H). 115 B 1HNMR (400MHz, DMSO-d6): δ: 11.45 (s, 1H), 11.06 (s, 1H), 14 8.18 (s, 1H),7.69-7.62 (m, 5H), 7.44 (s, 1H), 7.34 (s, 1H), 7.27 (s, 2H), 5.86 (s,1H), 5.09-5.06 (m, 1H), 4.36-4.29 (m, 4H), 3.85-3.82 (m, 2H), 3.43 (s,4H), 3.26-2.85 (m, 11H), 2.68-2.55 (m, 3H), 2.25 (s, 3H), 2.21 (s, 3H),2.11 (s, 3H), 2.10-2.00 (m, 3H), 1.91-1.88 (m, 3H), 1.68-1.65 (m, 2H),1.54-1.51 (m, 3H), 1.44-1.38 (m, 2H), 0.95-0.91 (m, 3H). 116 A 1HNMR(400 MHz, CDCl3): δ: 8.68 (s, 1H), 7.24-7.45 (m, 14H), 2 7.12 (s, 1H),5.92 (s, 1H), 5.07 (t, J = 8.4 Hz, 1H), 4.70 (t, J = 8.0 Hz, 1H),4.50-4.58 (m, 4H), 3.93-4.15 (m, 6H), 3.56-3.65 (m, 6H), 3.32 (t, J =5.6 Hz, 2H), 3.08-3.10 (m, 2H), 2.52-2.66 (m, 8H), 2.42 (s, 3H), 2.35(s, 3H), 2.20 (s, 3H), 2.00-2.02 (m, 2H), 1.64 (s, 4H), 1.45 (d, J = 6.8Hz, 4H), 1.05 (s, 9H), 0.87-0.89 (m, 3H). 117 A 1H NMR (400 MHz, CD3OD):δ 8.88 (s, 1H), 7.57-7.59 (m, 2H), 2 7.38-7.46 (m, 7H), 7.34 (s, 1H),6.13 (s, 1H), 4.96-5.01 (m, 1H), 4.71 (s, 1H), 4.51-4.58 (m, 9H),3.82-4.03 (m, 5H), 3.61-3.74 (m, 7H), 3.24-3.26 (m, 2H), 2.71-3.16 (m,10H), 2.48 (m, 3H), 2.41 (s, 3H), 2.34 (s, 3H), 2.18-2.26 (m, 4H),1.90-2.09 (m, 2H), 1.49 (d, J = 7.2 Hz, 3H), 1.39 (d, J = 5.6 Hz, 6H),1.05 (s, 9H), 0.92 (m, 3H). 118 A 1H NMR (400 MHz, CDCl3): δ: 8.83 (s,1H), 7.55 (d, J = 7.7 Hz, 2 2H), 7.47 (d, J = 7.8 Hz, 2H), 7.43 (d, J =7.8 Hz, 1H), 7.37 (s, 4H), 7.26 (s, 4H), 7.18 (d, J = 8.8 Hz, 1H), 6.91(s, 1H), 6.45 (s, 1H), 5.04-5.11 (m, 1H), 4.73 (t, J = 8.2 Hz, 1H), 4.65(d, J = 9.2 Hz, 1H), 4.57 (d, J = 5.2 Hz, 2H), 4.48 (s, 1H), 4.21 (m,2H), 3.91-4.09 (m, 6H), 3.65 (m, 5H), 3.52 (s, 4H), 3.27-3.37 (m, 4H),3.07-3.20 (m, 3H), 2.61 (s, 3H), 2.52 (s, 3H), 2.43 (s, 3H), 2.36 (s,3H), 2.33 (s, 1H), 2.12-2.27 (m, 2H), 2.00-2.03 (m, 2H), 1.66-1.73 (m,4H), 1.03 (s, 9H), 0.88-0.94 (m, 3H). 119 B 1H NMR (400 MHz, CDCl3): δ:8.67 (s, 1H), 7.22-7.42 (m, 2 10H), 6.89 (d, J = 4.4 Hz, 2H), 5.92 (s,1H), 5.45 (s, 1H), 5.02-5.10 (m, 1H), 4.83 (t, J = 8.0 Hz, 1H), 4.73 (d,J = 9.0 Hz, 1H), 4.40-4.64 (m, 3H), 3.91-4.08 (m, 7H), 3.31-3.69 (m,12H), 3.00-3.09 (m, 6H), 2.50 (s, 3H), 2.43 (s, 3H), 2.37 (s, 3H), 2.20(s, 3H), 2.03-2.20 (m, 3H), 1.60-1.68 (m, 5H), 1.47 (d, J = 4.0 Hz, 6H),1.33 (s, 1H), 1.04 (s, 9H). *Protein degradation range at indicatedconcentration (relative to DMSO control): A = degradation more than 60%;B = degradation between 30% and 60%; C = degradation between 0% and 30%.

Specific Embodiments of the Present Disclosure

The present disclosure encompasses the following specific embodiments.These following embodiments may include all of the features recited in aproceeding embodiment, as specified. Where applicable, the followingembodiments may also include the features recited in any proceedingembodiment inclusively or in the alternative.

In certain embodiments, the description provides an EZH2 PROTACmolecules selected from compounds 1-119 of Table 1 or 2, includingsalts, prodrugs, polymorphs, analogs, derivatives, and deuterated formsthereof.

As such, the description provides a compound comprising the structure ofany one of compounds 1-119 (i.e., any compound of Table 1 or 2),including salts, prodrugs, polymorphs, analogs, derivatives, anddeuterated forms thereof therapeutic compositions comprising the same,and methods of use as described herein.

In an aspect, the present disclosure provides a bifunctional compoundhaving the chemical structure:ULM-L-PTM,or a pharmaceutically acceptable salt, enantiomer, stereoisomer,solvate, polymorph or prodrug thereof, wherein: the ULM is a smallmolecule E3 ubiquitin ligase binding moiety that binds an E3 ubiquitinligase; the PTM is a small molecule comprising a enhancer of zestehomolog 2 (EZH2) protein targeting moiety; and the L is a bond or achemical linking moiety connecting the ULM and the PTM.

In any aspect or embodiment described herein, the E3 ubiquitin ligasebinding moiety that targets an E3 ubiquitin ligase selected from thegroup consisting of Von Hippel-Lindau (VLM), cereblon (CLM), mousedouble-minute homolog2 (MLM), and IAP (ILM).

In any aspect or embodiment described herein, the PTM or EBM isrepresented by Formula PTM-I, PTM-II, PTM-III, PTM-IVa, PTM-IVb, PTM-V,or PTM-VI:

wherein:

-   -   W_(PTM), X_(PTM), Y_(PTM), and Z_(PTM) are independently chosen        from C or N, wherein no more than two of W_(PTM), X_(PTM),        Y_(PTM), and Z_(PTM) is N;    -   X_(PTM1) is absent, NH, O, heterocycle (e.g., a 4-6 member        heterocyclic, such as a heterocyclic group with 1-3        N-substitutions);    -   X_(PTM2) is absent, CH₂, NH, O, heterocycle (e.g., a 4-6 member        heterocyclic, such as a heterocyclic group with 1-3        N-substitutions), heteroaryl (e.g., a 4-6 member heteroaryl,        such as a heteroaryl group with 1-3 N-substitutions), or        CH₂-heteroaryl (e.g., a 4-6 member heteroaryl, such as a        heteroaryl group with 1-3 N-substitutions);    -   R_(PTM) is absent, H, short chain alkyl (linear, branched,        optionally substituted), methoxy, or ethoxy;    -   R_(PTM1) is an absent, alkyl, halogen, haloalkyl, or alkoxy;    -   R_(PTM2) and R_(PTM3) are independently a halogen, CN, alkoxy        (e.g., methoxy or ethoxy);    -   R_(PTM4) is a alkyl (linear, branched, optionally substituted)        or a 4-6 member cyclicalkyl

is an optionally substituted C₁-C₄ alkyl that is optionally cyclized tothe adjacent carbon of the pyridinyl ring to which it is attached; and

-   -   indicates a covalent linkage to at least one of a linker (L), a        ULM, a ULM′, a VLM, a VLM′, a CLM, a CLM′, an ILM, an ILM′, a        MLM, a MLM′, or a combination thereof.

In any aspect or embodiment described herein, the

is a methyl group.

In any aspect or embodiment described herein, the ULM is a VonHippel-Lindau (VHL) ligase-binding moiety (VLM) with a chemicalstructure represented by:

wherein:

-   -   X¹, X² are each independently selected from the group of a bond,        O, NR³, CR^(Y3)R^(Y4), C═O, C═S, SO, and SO₂;    -   R^(Y3), R^(Y4) are each independently selected from the group of        H, linear or branched C₁₋₆ alkyl, optionally substituted by 1 or        more halo, optionally substituted C₁₋₆ alkoxyl (e.g., optionally        substituted by 0-3R^(P) groups);    -   R^(P) is 0, 1, 2, or 3 groups each independently selected from        the group H, halo, —OH, C₁₋₃ alkyl, C═O;    -   W³ is selected from the group of an optionally substituted        -T-N(R^(1a)R^(1b))X³, optionally substituted-T-N(R^(1a)R^(1b)),        optionally substituted -T-Aryl, an optionally substituted        -T-Heteroaryl, an optionally substituted T-biheteroaryl, an        optionally substituted -T-Heterocycle, an optionally substituted        -T-biheterocycle, an optionally substituted —NR¹-T-Aryl, an        optionally substituted —NR¹-T-Heteroaryl or an optionally        substituted —NR¹-T-Heterocycle;    -   X³ is C═O, R¹, R^(1a), R^(1b);    -   each of R¹, R^(1a), R^(1b) is independently selected from the        group consisting of H, linear or branched C₁-C₆ alkyl group        optionally substituted by 1 or more halo or —OH groups,        R^(Y3)C═O, R^(Y3)C═S, R^(Y3)SO, R^(Y3)SO₂, N(R^(Y3)R^(Y4))C═O,        N(R^(Y3)R^(Y4))C═S, N(R^(Y3)R^(Y4))SO, and N(R^(Y3)R^(Y4))SO₂;    -   T is selected from the group of an optionally substituted alkyl,        —(CH₂)_(n)— group, wherein each one of the methylene groups is        optionally substituted with one or two substituents selected        from the group of halogen, methyl, a linear or branched C₁-C₆        alkyl group optionally substituted by 1 or more halogen or —OH        groups or an amino acid side chain optionally substituted; and    -   n is 0 to 6,    -   W⁴ is

-   -   R_(14a), R_(14b), are each independently selected from the group        of H, haloalkyl, or optionally substituted alkyl;    -   W⁵ is selected from the group of a phenyl or a 5-10 membered        heteroaryl,    -   R₁₅ is selected from the group of H, halogen, CN, OH, NO₂, N        R_(14a)R_(14b), OR_(14a), CONR_(14a)R_(14b), NR_(14a)COR_(14b),        SO₂NR_(14a)R_(14b), NR_(14a) SO₂R_(14b), optionally substituted        alkyl, optionally substituted haloalkyl, optionally substituted        haloalkoxy; aryl, heteroaryl, cycloalkyl, or cycloheteroalkyl        (each optionally substituted); and    -   the dashed line indicates the site of attachment of at least one        PTM, another ULM (ULM′) or a chemical linker moiety coupling at        least one PTM or a ULM′ or both to ULM.

In any aspect or embodiment described herein, the ULM is a VonHippel-Lindau (VHL) ligase-binding moiety (VLM) with a chemicalstructure represented by:

wherein:

-   -   W³ is selected from the group of an optionally substituted aryl,        optionally substituted heteroaryl, or

-   -   R₉ and R₁₀ are independently hydrogen, optionally substituted        alkyl, optionally substituted cycloalkyl, optionally substituted        hydroxyalkyl, optionally substituted heteroaryl, or haloalkyl,        or R₉, R₁₀, and the carbon atom to which they are attached form        an optionally substituted cycloalkyl;    -   R₁₁ is selected from the group of an optionally substituted        heterocyclic, optionally substituted alkoxy, optionally        substituted heteroaryl, optionally substituted aryl,

-   -   R₁₂ is selected from the group of H or optionally substituted        alkyl;    -   R₁₃ is selected from the group of H, optionally substituted        alkyl, optionally substituted alkylcarbonyl, optionally        substituted (cycloalkyl)alkylcarbonyl, optionally substituted        aralkylcarbonyl, optionally substituted arylcarbonyl, optionally        substituted (heterocyclyl)carbonyl, or optionally substituted        aralkyl;    -   R_(14a), R_(14b), are each independently selected from the group        of H, haloalkyl, or optionally substituted alkyl;    -   W⁵ is selected from the group of a phenyl or a 5-10 membered        heteroaryl,    -   R₁₅ is selected from the group of H, halogen, CN, OH, NO₂, N        R_(14a)R_(14b), OR_(14a), CONR_(14a)R_(14b), NR_(14a)COR_(14b),        SO₂NR_(14a)R_(14b), NR_(14a) SO₂R_(14b), optionally substituted        alkyl, optionally substituted haloalkyl, optionally substituted        haloalkoxy; aryl, heteroaryl, cycloalkyl, or cycloheteroalkyl        (optionally substituted);    -   R₁₆ is independently selected from the group of halo, optionally        substituted alkyl, optionally substituted haloalkyl, hydroxy, or        optionally substituted haloalkoxy;    -   o is 0, 1, 2, 3, or 4;    -   R₁₈ is independently selected from the group of H, halo,        optionally substituted alkoxy, cyano, optionally substituted        alkyl, haloalkyl, haloalkoxy or a linker; and    -   p is 0, 1, 2, 3, or 4, and wherein the dashed line indicates the        site of attachment of at least one PTM, another ULM (ULM′) or a        chemical linker moiety coupling at least one PTM or a ULM′ or        both to ULM.

The compound of any of the claims 1-5, wherein the ULM has a chemicalstructure selected from the group of:

wherein:

-   -   R₁ is H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl,        cyclobutyl, cyclopentyl, or cyclohexyl; optionally substituted        alkyl, optionally substituted hydroxyalkyl, optionally        substituted heteroaryl, or haloalkyl;    -   R_(14a) is H, haloalkyl, optionally substituted alkyl, methyl,        fluoromethyl, hydroxymethyl, ethyl, isopropyl, or cyclopropyl;    -   R₁₅ is selected from the group consisting of H, halogen, CN, OH,        NO₂, optionally substituted heteroaryl, optionally substituted        aryl; optionally substituted alkyl, optionally substituted        haloalkyl, optionally substituted haloalkoxy, cycloalkyl, or        cycloheteroalkyl (optionally substituted);    -   X is C, CH₂, or C═O    -   R³ is absent or an optionally substituted 5 or 6 membered        heteroaryl; and    -   the dashed line indicates the site of attachment of at least one        PTM, another ULM (ULM′) or a chemical linker moiety coupling at        least one PTM or a ULM′ or both to the ULM.

In any aspect or embodiment described herein, the ULM comprises a groupaccording to the chemical structure:

wherein:

-   -   R_(14a) is H, haloalkyl, optionally substituted alkyl, methyl,        fluoromethyl, hydroxymethyl, ethyl, isopropyl, or cyclopropyl;    -   R9 is H;    -   R10 is H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl,        cyclobutyl, cyclopentyl, or cyclohexyl;    -   R11 is

optionally substituted heteroaryl;

-   -   p is 0, 1, 2, 3, or 4; and    -   each R₁₈ is independently halo, optionally substituted alkoxy,        cyano, optionally substituted alkyl, haloalkyl, haloalkoxy or a        linker;    -   R12 is H, C═O    -   R13 is H, optionally substituted alkyl, optionally substituted        alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl,        optionally substituted aralkylcarbonyl, optionally substituted        arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or        optionally substituted aralkyl,    -   R₁₅ is selected from the group consisting of H, halogen, Cl, CN,        OH, NO₂, optionally substituted heteroaryl, optionally        substituted aryl;

-   -   and wherein the dashed line indicates the site of attachment of        at least one PTM, another ULM (ULM′) or a chemical linker moiety        coupling at least one PTM or a ULM′ or both to the ULM.

In any aspect or embodiment described herein, the ULM is a cereblon E3ligase-binding moiety (CLM) selected from the group consisting of athalidomide, lenalidomide, pomalidomide, analogs thereof, isosteresthereof, or derivatives thereof.

In any aspect or embodiment described herein, the CLM has a chemicalstructure represented by:

wherein:

-   -   W is selected from the group consisting of CH₂, CHR, C═O, SO₂,        NH, and N-alkyl;    -   each X is independently selected from the group consisting of O,        S, and H₂;    -   Y is selected from the group consisting of CH₂, —C═CR′, NH,        N-alkyl, N-aryl, N-hetaryl, N-cycloalkyl, N-heterocyclyl, O, and        S;    -   Z is selected from the group consisting of O, S, and H₂;    -   G and G′ are independently selected from the group consisting of        H, alkyl (linear, branched, optionally substituted), OH,        R′OCOOR, R′OCONRR″, CH₂-heterocyclyl optionally substituted with        R′, and benzyl optionally substituted with R′;    -   Q₁, Q₂, Q₃, and Q₄ represent a carbon C substituted with a group        independently selected from R′, N or N-oxide;    -   A is independently selected from the group H, alkyl (linear,        branched, optionally substituted), cycloalkyl, C₁ and F;    -   R comprises —CONR′R″, —OR′, —NR′R″, —SR′, —SO₂R′, —SO₂NR′R″,        —CR′R″—, —CR′NR′R″—, (—CR′O)_(n)R″, -aryl, -hetaryl, -alkyl        (linear, branched, optionally substituted), -cycloalkyl,        -heterocyclyl, —P(O)(OR′)R″, —P(O)R′R″, —OP(O)(OR′)R″,        —OP(O)R′R″, —Cl, —F, —Br, —I, —CF₃, —CN, —NR′SO₂NR′R″,        —NR′CONR′R″, —CONR′COR″, —NR′C(═N—CN)NR′R″, —C(═N—CN)NR′R″,        —NR′C(═N—CN)R″, —NR′C(═C—NO₂)NR′R″, —SO₂NR′COR″, —NO₂, —CO₂R′,        —C(C═N—OR′)R″, —CR′═CR′R″, —CCR′, —S(C═O)(C═N—R′)R″, —SF₅ and        —OCF₃;    -   R′ and R″ are independently selected from the group consisting        of a bond, H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic,        —C(═O)R, heterocyclyl, each of which is optionally substituted;    -   represents a bond that may be stereospecific ((R) or (S)) or        non-stereospecific; and    -   R_(n) comprises a functional group or an atom,    -   wherein n is an integer from 1-10 (e.g., 1-4, 1, 2, 3, 4, 5, 6,        7, 8, 9, or 10), and wherein    -   when n is 1, R_(n) is modified to be covalently joined to the        linker group (L), and    -   when n is 2, 3, or 4, then one R_(n) is modified to be        covalently joined to the linker group (L), and any other R_(n)        is optionally modified to be covalently joined to a PTM, a CLM,        a second CLM having the same chemical structure as the CLM, a        CLM′, a second linker, or any multiple or combination thereof.

In any aspect or embodiment described herein, the CLM has a chemicalstructure represented by:

wherein:

-   -   W is independently selected from the group CH₂, C═O, NH, and        N-alkyl;    -   R is independently selected from a H, methyl, optionally        substituted alkyl (e.g., C₁-C₆ alkyl (linear, branched,        optionally substituted));    -   represents a bond that may be stereospecific ((R) or (S)) or        non-stereospecific; and    -   Rn comprises 1-4 independently selected functional groups or        atoms, and optionally, one of which is modified to be covalently        joined to a PTM, a chemical linker group (L), a CLM (or CLM′) or        combination thereof.

In any aspect or embodiment described herein, the ULM is a (MDM2)binding moiety (MLM) as described in the present disclosure (e.g., theMLM has a chemical moiety selected from the group consisting of asubstituted imidazolines, a substituted spiro-indolinones, a substitutedpyrrolidines, a substituted piperidinones, a substituted morpholinones,a substituted pyrrolopyrimidines, a substituted imidazolopyridines, asubstituted thiazoloimidazoline, a substituted pyrrolopyrrolidinones,and a substituted isoquinolinones).

In any aspect or embodiment described herein, the MLM has a structureselected from the group consisting of:

wherein:

-   -   X is selected from the group consisting of carbon, oxygen,        sulfur, sulfoxide, sulfone, and N—R^(a);    -   R^(a) is independently H or an alkyl group with carbon number 1        to 6;    -   Y and Z are independently carbon or nitrogen;    -   A, A′ and A″ are independently selected from C, N, O or S, can        also be one or two atoms forming a fused bicyclic ring, or a        6,5- and 5,5-fused aromatic bicyclic group;    -   R₁, R₂ are independently selected from the group consisting of        an aryl or heteroaryl group, a heteroaryl group having one or        two heteroatoms independently selected from sulfur or nitrogen,        wherein the aryl or heteroaryl group can be mono-cyclic or        bi-cyclic, or unsubstituted or substituted with one to three        substituents independently selected from the group consisting        of: halogen, —CN, C1 to C6 alkyl group, C3 to C6 cycloalkyl,        —OH, alkoxy with 1 to 6 carbons, fluorine substituted alkoxy        with 1 to 6 carbons, sulfoxide with 1 to 6 carbons, sulfone with        1 to 6 carbons, ketone with 2 to 6 carbons, amides with 2 to 6        carbons, and dialkyl amine with 2 to 6 carbons;    -   R₃, R₄ are independently selected from the group consisting of        H, methyl and C1 to C6 alkyl;    -   R₅ is selected from the group consisting of an aryl or        heteroaryl group, a heteroaryl group having one or two        heteroatoms independently selected from sulfur or nitrogen,        wherein the aryl or heteroaryl group can be mono-cyclic or        bi-cyclic, or unsubstituted or substituted with one to three        substituents independently selected from the group consisting        of: halogen, —CN, C1 to C6 alkyl group, C3 to C6 cycloalkyl,        —OH, alkoxy with 1 to 6 carbons, fluorine substituted alkoxy        with 1 to 6 carbons, sulfoxide with 1 to 6 carbons, sulfone with        1 to 6 carbons, ketone with 2 to 6 carbons, amides with 2 to 6        carbons, dialkyl amine with 2 to 6 carbons, alkyl ether (C2 to        C6), alkyl ketone (C3 to C6), morpholinyl, alkyl ester (C3 to        C6), alkyl cyanide (C3 to C6);    -   R₆ is H or —C(═O)R^(b), wherein    -   R^(b) is selected from the group consisting of alkyl,        cycloalkyl, mono-, di- or tri-substituted aryl or heteroaryl,        4-morpholinyl, 1-(3-oxopiperazunyl), 1-piperidinyl,        4-N—R^(c)-morpholinyl, 4-R^(c)-1-piperidinyl, and        3-R′-1-piperidinyl, wherein    -   R^(c) is selected from the group consisting of alkyl, fluorine        substituted alkyl, cyano alkyl, hydroxyl-substituted alkyl,        cycloalkyl, alkoxyalkyl, amide alkyl, alkyl sulfone, alkyl        sulfoxide, alkyl amide, aryl, heteroaryl, mono-, bis- and        tri-substituted aryl or heteroaryl, CH2CH2R^(d), and        CH2CH2CH2R^(d), wherein    -   R^(d) is selected from the group consisting of alkoxy, alkyl        sulfone, alkyl sulfoxide, N-substituted carboxamide,        —NHC(O)-alkyl, —NH—SO₂-alkyl, aryl, substituted aryl,        heteroaryl, substituted heteroaryl;    -   R₇ is selected from the group consisting of H, C1 to C6 alkyl,        cyclic alkyl, fluorine substituted alkyl, cyano substituted        alkyl, 5- or 6-membered hetero aryl or aryl, substituted 5- or        6-membered hetero aryl or aryl;    -   R₈ is selected from the group consisting of —R^(e)—C(O)—R^(f),        —R^(e)-alkoxy, —R^(e)-aryl, —R^(e)-heteroaryl, and        —R^(e)—C(O)—R^(f)—C(O)—R^(g), wherein:        -   R^(e) is an alkylene with 1 to 6 carbons, or a bond;        -   R^(f) is a substituted 4- to 7-membered heterocycle;    -   R^(g) is selected from the group consisting of aryl, hetero        aryl, substituted aryl or heteroaryl, and 4- to 7-membered        heterocycle;    -   R₉ is selected from the group consisting of a mono-, bis- or        tri-substituent on the fused bicyclic aromatic ring in Formula        (A-3), wherein the substitutents are independently selected from        the group consisting of halogen, alkene, alkyne, alkyl,        unsubstituted or substituted with Cl or F;    -   R₁₀ is selected from the group consisting of an aryl or        heteroaryl group, wherein the heteroaryl group can contain one        or two heteroatoms as sulfur or nitrogen, aryl or heteroaryl        group can be mono-cyclic or bi-cyclic, the aryl or heteroaryl        group can be unsubstituted or substituted with one to three        substituents, including a halogen, F, Cl, —CN, alkene, alkyne,        C1 to C6 alkyl group, C1 to C6 cycloalkyl, —OH, alkoxy with 1 to        6 carbons, fluorine substituted alkoxy with 1 to 6 carbons,        sulfoxide with 1 to 6 carbons, sulfone with 1 to 6 carbons,        ketone with 2 to 6 carbons;    -   R₁₁ is —C(O)—N(R^(h))(R^(i)), wherein R^(h) and R^(i) are        selected from groups consisting of the following: H, C1 to C6        alkyl, alkoxy substituted alkyl, sulfone substituted alkyl,        aryl, heterol aryl, mono-, bis- or tri-substituted aryl or        hetero aryl, alkyl carboxylic acid, heteroaryl carboxylic acid,        alkyl carboxylic acid, fluorine substituted alkyl carboxylic        acid, aryl substituted cycloalkyl, hetero aryl substituted        cycloalkyl; wherein R^(h) and R^(i) are independently selected        from the group consisting of H, connected to form a ring,        4-hydroxycyclohehexane; mono- and di-hydroxy substituted alkyl        (C3 to C6); 3-hydroxycyclobutane; phenyl-4-carboxylic acid, and        substituted phenyl-4-carboxylic acid;    -   R₁₂ and R₁₃ are independently selected from H, lower alkyl (C1        to C6), lower alkenyl (C2 to C6), lower alkynyl (C2 to C6),        cycloalkyl (4, 5 and 6-membered ring), substituted cycloalkyl,        cycloalkenyl, substituted cycloalkenyl, 5- and 6-membered aryl        and heteroaryl, R¹² and R¹³ can be connected to form a 5- and        6-membered ring with or without substitution on the ring;    -   R₁₄ is selected from the group consisting of alkyl, substituted        alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl,        heteroaryl, substituted heteroaryl, heterocycle, substituted        heterocycle, cycloalkyl, substituted cycloalkyl, cycloalkenyl        and substituted cycloalkenyl;    -   R₁₅ is CN;    -   R₁₆ is selected from the group consisting of C1-6 alkyl, C1-6        cycloalkyl, C2-6 alkenyl, C1-6 alkyl or C3-6 cycloalkyl with one        or multiple hydrogens replaced by fluorine, alkyl or cycloalkyl        with one CH₂ replaced by S(═O), —S, or —S(═O)₂, alkyl or        cycloalkyl with terminal CH₃ replaced by S(═O)2N(alkyl)(alkyl),        —C(═O)N(alkyl)(alkyl), —N(alkyl)S(═O)2(alkyl), —C(═O)2(alkyl),        —O(alkyl), C1-6 alkyl or alkyl-cycloalkyl with hydron replaced        by hydroxyl group, a 3 to 7 membered cycloalkyl or        heterocycloalkyl, optionally containing a —(C═O)— group, or a 5        to 6 membered aryl or heteroaryl group, which heterocycloalkyl        or heteroaryl group can contain from one to three heteroatoms        independently selected from O, N or S, and the cycloalkyl,        heterocycloalkyl, aryl or heteroaryl group can be unsubstituted        or substituted with from one to three substituents independently        selected from halogen, C1-6 alkyl groups, hydroxylated C1-6        alkyl, C1-6 alkyl containing thioether, ether, sulfone,        sulfoxide, fluorine substituted ether or cyano group;    -   R₁₇ is selected from the group consisting of        (CH₂)nC(O)NR^(k)R^(l), wherein R^(k) and R^(l) are independently        selected from H, C1-6 alkyl, hydroxylated C1-6 alkyl, C1-6        alkoxy alkyl, C1-6 alkyl with one or multiple hydrogens replaced        by fluorine, C1-6 alkyl with one carbon replaced by S(O),        S(O)(O), C1-6 alkoxyalkyl with one or multiple hydrogens        replaced by fluorine, C1-6 alkyl with hydrogen replaced by a        cyano group, 5 and 6 membered aryl or heteroaryl, alkyl aryl        with alkyl group containing 1-6 carbons, and alkyl heteroaryl        with alkyl group containing 1-6 carbons, wherein the aryl or        heteroaryl group can be further substituted;    -   R₁₈ is selected from the group consisting of substituted aryl,        heteroaryl, alkyl, cycloalkyl, the substitution is preferably        —N(C1-4 alkyl)(cycloalkyl), —N(C1-4 alkyl)alkyl-cycloalkyl, and        —N(C1-4 alkyl)[(alkyl)-(heterocycle-substituted)-cycloalkyl];    -   R₁₉ is selected from the group consisting of aryl, heteroaryl,        bicyclic heteroaryl, and these aryl or heteroaryl groups can be        substituted with halogen, C1-6 alkyl, C1-6 cycloalkyl, CF₃, F,        CN, alkyne, alkyl sulfone, the halogen substitution can be mon-        bis- or tri-substituted;    -   R₂₀ and R₂₁ are independently selected from C1-6 alkyl, C1-6        cycloalkyl, C1-6 alkoxy, hydoxylated C1-6 alkoxy, and fluorine        substituted C1-6 alkoxy, wherein R₂₀ and R₂₁ can further be        connected to form a 5, 6 and 7-membered cyclic or heterocyclic        ring, which can further be substituted;    -   R₂₂ is selected from the group consisting of H, C1-6 alkyl, C1-6        cycloalkyl, carboxylic acid, carboxylic acid ester, amide,        reverse amide, sulfonamide, reverse sulfonamide, N-acyl urea,        nitrogen-containing 5-membered heterocycle, the 5-membered        heterocycles can be further substituted with C1-6 alkyl, alkoxy,        fluorine-substituted alkyl, CN, and alkylsulfone;    -   R₂₃ is selected from aryl, heteroaryl, —O-aryl, —O-heteroaryl,        —O-alkyl, —O-alkyl-cycloalkyl, —NH-alkyl, —NH-alkyl-cycloalkyl,        —N(H)-aryl, —N(H)-heteroaryl, —N(alkyl)-aryl,        —N(alkyl)-heteroaryl, the aryl or heteroaryl groups can be        substituted with halogen, C1-6 alkyl, hydoxylated C1-6 alkyl,        cycloalkyl, fluorine-substituted C1-6 alkyl, CN, alkoxy, alkyl        sulfone, amide and sulfonamide;    -   R₂₄ is selected from the group consisting of —CH2-(C1-6 alkyl),        —CH2-cycloalkyl, -CH2-aryl, CH2-heteroaryl, where alkyl,        cycloalkyl, aryl and heteroaryl can be substituted with halogen,        alkoxy, hydoxylated alkyl, cyano-substituted alkyl, cycloalyl        and substituted cycloalky;    -   R₂₅ is selected from the group consisting of C1-6 alkyl, C1-6        alkyl-cycloalkyl, alkoxy-substituted alkyl, hydroxylated alkyl,        aryl, heteroaryl, substituted aryl or heteroaryl, 5,6, and        7-membered nitrogen-containing saturated heterocycles, 5,6-fused        and 6,6-fused nitrogen-containing saturated heterocycles and        these saturated heterocycles can be substituted with C1-6 alkyl,        fluorine-substituted C1-6 alkyl, alkoxy, aryl and heteroaryl        group;    -   R₂₆ is selected from the group consisting of C1-6 alkyl, C3-6        cycloalkyl, the alkyl or cycloalkyl can be substituted with —OH,        alkoxy, fluorine-substituted alkoxy, fluorine-substituted alkyl,        —NH₂, —NH-alkyl, NH—C(O)alkyl, —NH—S(O)2-alkyl, and        —S(O)2-alkyl;    -   R²⁷ is selected from the group consisting of aryl, heteroaryl,        bicyclic heteroaryl, wherein the aryl or heteroaryl groups can        be substituted with C1-6 alkyl, alkoxy, NH2, NH-alkyl, halogen,        or —CN, and the substitution can be independently mono-, bis-        and tri-substitution;    -   R₂₈ is selected from the group consisting of aryl, 5 and        6-membered heteroaryl, bicyclic heteroaryl, cycloalkyl,        saturated heterocycle such as piperidine, piperidinone,        tetrahydropyran, N-acyl-piperidine, wherein the cycloalkyl,        saturated heterocycle, aryl or heteroaryl can be further        substituted with —OH, alkoxy, mono-, bis- or tri-substitution        including halogen, —CN, alkyl sulfone, and fluorine substituted        alkyl groups; and    -   R_(1″) is selected from the group consisting of alkyl, aryl        substituted alkyl, alkoxy substituted alkyl, cycloalkyl,        aryl-substituted cycloalkyl, and alkoxy substituted cycloalkyl,        or a pharmaceutically acceptable salt, enantiomer, stereoisomer,        solvate, polymorph or prodrug thereof.

In any aspect or embodiment described herein, the heterocycles in R^(f)and R^(g) are independently selected from the group consisting ofsubstituted pyrrolidine, substituted piperidine, and substitutedpiperizine.

In any aspect or embodiment described herein, the R₉ substituents areselected from Cl and F.

In any aspect or embodiment described herein, the R₁₀ substituents areselected from H, F and Cl.

In any aspect or embodiment described herein, R^(h) and R^(i) areselected from the group consisting of:

-   -   (i) R^(h) is H, and R^(i) is 4-hydroxycyclohehexane;    -   (ii) R^(h) is H, and R^(i) is mono- and di-hydroxy substituted        lower alkyl (C3 to C6);    -   (iii) R^(h) is H, and R^(i) is 3-hydroxycyclobutane; and    -   (iv) R^(h) is H, and R^(i) is phenyl-4-carboxylic acid,        substituted phenyl-4-carboxylic acid.

In any aspect or embodiment described herein, the R₁₈ substitution isselected from the group consisting of —N(C1-4 alkyl)(cycloalkyl),—N(C1-4 alkyl)alkyl-cycloalkyl, and —N(C1-4alkyl)[(alkyl)-(heterocycle-substituted)-cycloalkyl].

In any aspect or embodiment described herein, the R₂₈ saturatedheterocycle is selected from piperidine, piperidinone, tetrahydropyran,and N-acyl-piperidine.

In any aspect or embodiment described herein, the compound has astructure selected from the group consisting of:

wherein:

-   -   R1′ and R2′ are independently selected from the group consisting        of F, Cl, Br, I, acetylene, CN, CF₃ and NO₂;    -   R3′ is selected from the group consisting of —OCH₃, —OCH₂CH₃,        —OCH₂CH₂F, —OCH₂CH₂OCH₃, and —OCH(CH₃)₂;    -   R4′ and R6′ are independently selected from the group consisting        of H, halogen, —CH₃, —CF₃, —OCH₃, —C(CH₃)₃, —CH(CH₃)₂,        -cyclopropyl, —CN, —C(CH₃)₂OH, —C(CH₃)₂OCH₂CH₃, —C(CH₃)₂CH₂OH,        —C(CH₃)₂CH₂OCH₂CH₃, —C(CH₃)₂CH₂CH₂CH₂OH, C(CH₃)₂CH₂OCH₂CH₃,        —C(CH₃)₂CN, —C(CH₃)₂C(O)CH₃, —C(CH₃)₂C(O)NHCH₃,        —C(CH₃)₂C(O)N(CH₃)₂, —SCH₃, —SCH₂CH₃, —S(O)₂CH₃, —S(O₂)CH₂CH₃,        —NHC(CH₃)₃, —N(CH₃)₂, pyrrolidinyl, and 4-morpholinyl; and    -   R5′ is selected from the group consisting of halogen,        -cyclopropyl, —S(O)₂CH₃, —S(O)₂CH₂CH₃, 1-pyrrolidinyl, —NH₂,        —N(CH₃)₂, and —NHC(CH₃)₃, or a pharmaceutically acceptable salt,        enantiomer, stereoisomer, solvate, polymorph or prodrug thereof.

In any aspect or embodiment described herein, the linker is attached toat least one of R1′, R2′, R3′, R4′, R5′, R6′, or a combination thereof.

In any aspect or embodiment described herein, R^(6′) is independentlyselected from the group consisting of H,

wherein * indicates the point of attachment of the linker.

In any aspect or embodiment described herein, the MLM has a structureselected from the group consisting of:

wherein

-   -   R_(7′) is a member selected from the group consisting of        halogen, mono-, and di- or tri-substituted halogen;    -   R_(8′) is selected from the group consisting of H, —F, —Cl, —Br,        —I, —CN, —NO₂, ethylnyl, cyclopropyl, methyl, ethyl, isopropyl,        vinyl, methoxy, ethoxy, isopropoxy, —OH, other C1-6 alkyl, other        C1-6 alkenyl, and C1-6 alkynyl, mono-, di- or tri-substituted;    -   R_(9′) is selected from the group consisting of alkyl,        substituted alkyl, alkenyl, substituted alkenyl, alkynyl,        substituted alkynyl, aryl, substituted aryl, hetero aryl,        substituted heteroaryl, cycloalkyl, substituted cycloalkyl,        alkenyl, and substituted cycloalkenyl;    -   Z is selected from the group consisting of H, —OCH₃, —OCH₂CH₃,        and halogen;    -   R_(10′) and R_(11′) are each independently selected from the        group consisting of H, (CH₂)_(n)—R′, (CH₂)_(n)—NR′R″,        (CH₂)_(n)—NR′COR″, (CH₂)_(n)—NR′SO₂R″, (CH₂)_(n)—COOH,        (CH₂)_(n)—COOR′, (CH)_(n)—CONR′R″, (CH₂)_(n)—OR′, (CH₂)_(n)—SR′,        (CH₂)_(n)—SOR′, (CH₂)_(n)—CH(OH)—R′, (CH₂)_(n)—COR′,        (CH₂)_(n)—SO₂R′, (CH₂)_(n)—SONR′R″, (CH₂)_(n)—SO₂NR′R″,        (CH₂CH₂O)_(m)—(CH₂)_(n)—R′, (CH₂CH₂O)_(m)—(CH₂)_(n)—OH,        (CH₂CH₂O)_(m)—(CH₂)_(n)—OR′, (CH₂CH₂O)_(m)—(CH₂)_(n)—NR′R″,        (CH₂CH₂O)_(m)—(CH₂)_(n)—NR′COR″,        (CH₂CH₂O)_(m)(CH₂)_(n)—NR′SO₂R″, (CH₂CH₂O)_(m)(CH₂)_(n)—COOH,        (CH₂CH₂O)_(m)(CH₂)_(n)—COOR′, (CH₂CH₂O)_(m)—(CH₂)_(n)—CONR′R″,        (CH₂CH₂O)_(m)—(CH₂)_(n)—SO₂R′, (CH₂CH₂O)_(m)—(CH₂)_(n)—COR′,        (CH₂CH₂O)_(m)—(CH₂)_(n)—SONR′R″,        (CH₂CH₂O)_(m)—(CH₂)_(n)—SO₂NR′R″,        (CH₂)_(p)—(CH₂CH₂O)_(m)—(CH₂)_(n)R′,        (CH₂)_(p)—(CH₂CH₂O)_(m)—(CH₂)_(n)—OH,        (CH₂)_(p)—(CH₂CH₂O)_(m)—(CH₂)_(n)—OR′,        (CH₂)_(p)—(CH₂CH₂O)_(m)—(CH₂)_(n)—NR′R″,        (CH₂)_(p)—(CH₂CH₂O)_(m)—(CH₂)_(n)—NR′COR″,        (CH₂)_(p)—(CH₂CH₂O)_(m)—(CH₂)_(n)—NR′SO₂R″,        (CH₂)_(p)—(CH₂CH₂O)_(m)—(CH₂)_(n)—COOH,        (CH₂)_(p)—(CH₂CH₂O)_(m)—(CH₂)_(n)—COOR′,        (CH₂)_(p)—(CH₂CH₂O)_(m)—(CH₂)_(n)—CONR′R″,        (CH₂)_(p)—(CH₂CH₂O)_(m)—(CH₂)_(n)—SO₂R′,        (CH₂)_(p)—(CH₂CH₂O)_(m)—(CH₂)_(n)—COR′,        (CH₂)_(p)—(CH₂CH₂O)_(m)—(CH₂)_(n)—SONR′R″,        (CH₂)_(p)—(CH₂CH₂O)_(m)—(CH₂)_(n)—SO₂NR′R″, Aryl-(CH₂)_(n)—COOH,        and heteroaryl-alkyl-CO-alkyl-NR′R″m, wherein the alkyl may be        substituted with OR′, and heteroaryl-(CH₂)_(n)-heterocycle        wherein the heterocycle may optionally be substituted with        alkyl, hydroxyl, COOR′ and COR′; wherein R′ and R″ are selected        from H, alkyl, alkyl substituted with halogen, hydroxyl, NH₂,        NH(alkyl), N(alkyl)₂, oxo, carboxy, cycloalkyl and heteroaryl;    -   m, n, and p are independently 0 to 6;    -   R_(12′) is selected from the group consisting of —O-(alkyl),        —O-(alkyl)-alkoxy, —C(O)-(alkyl), —C(OH)-alkyl-alkoxy,        —C(O)—NH-(alkyl), —C(O)—N-(alkyl)2, —S(O)-(alkyl),        S(O)2-(alkyl), —C(O)-(cyclic amine), and —O-aryl-(alkyl),        —O-aryl-(alkoxy); and    -   R_(1″) is selected from the group consisting of alkyl, aryl        substituted alkyl, alkoxy substituted alkyl, cycloalkyl,        aryl-substituted cycloalkyl, and alkoxy substituted cycloalkyl,        or a pharmaceutically acceptable salt, enantiomer, stereoisomer,        solvate, polymorph or prodrug thereof.

In any aspect or embodiment described herein, the linker is attached toat least one of Z, R_(8′), R_(9′), R_(10′), R_(11′), R_(12′), R₁″, or acombination thereof.

In any aspect or embodiment described herein, the ULM is a IAP E3ubiquitin ligase binding moiety (ILM) as described in the presentdisclosure (e.g., the ILM comprises the amino acids alanine (A), valine(V), proline (P), and isoleucine (I) or their unnatural mimetics).

In any aspect or embodiment described herein, the ULM is a IAP E3ubiquitin ligase binding moiety (ILM) comprising a AVPI tetrapeptidefragment or derivative thereof.

In any aspect or embodiment described herein, the ILM may have achemical structure represented by:

wherein:

-   -   PTM is a protein target moiety that binds to a target protein or        a target polypeptide;    -   L is a linker group coupling PTM to the ILM molecule shown;    -   R₁ is, independently, H, C₁-C₄-alky, Q-Cvalkenyl, C₁-C₄-alkynyl        or C₃-C₁₀-cycloalkyl which are unsubstituted or substituted;    -   R₂ is, independently, H. C₁-C₄-alkyl, C₁-C₄-alkenyl,        C₁-C₄-alkynyl or C₃-C₁₀-cycloalkyl which are unsubstituted or        substituted;    -   R₃ is, independently. H, —CF₃, —C₂H₅, C₁-C₄-alkyl.        C₁-C₄-alkenyl, C₁-C₄-alkynyl, —CH₂—Z or any R₂ and R₃ together        form a heterocyclic ring:    -   Z is, independently. H, —OH, F, Cl—CH₃—CF₃—CH₂Cl—CH₂F or —CH₂OH;    -   R₄ is, independently, C₁-C₁₆ straight or branched alkyl,        C₁-C₁₆-alkenyl. C₁-C₁₆-alkynyl. C₃-C₁₀-cycloalkyl, —(CH₂)₀₋₆—Z₁,        —(CH₂)₀₋₆-aryl and —(CH₂)₀₋₆-het, wherein alkyl, cycloalkyl, and        phenyl are unsubstituted or substituted;    -   R₅ is, independently. H. C₁₋₁₀-alkyl, aryl, phenyl,        C₃₋₇-cycloalkyl, —(CH₂)₁₋₆—C₃₋₇-cycloalkyl. —C₁₋₁₀-alkyl-aryl,        —(CH₂)₀₋₆—C₃₋₇-cycloalkyl-(CH₂)₀₋₆-phenyl,        —(CH₂)₀₋₄—CH[(CH₂)₁₋₄-phenyl]₂, indanyl, —C(O)—C₁₋₁₀-alkyl,        —C(O)—(CH₂)₁₋₆—C₃₋₇-cycloalkyl, —C(O)—(CH₂)₀₋₆-phenyl,        —(CH₂)₀₋₆—C(O)-phenyl, —(CH₂)₀₋₆-het, —C(O)—(CH₂)₁₋₆-het, or R₅        is a residue of an amino acid, wherein the alkyl, cycloalkyl,        phenyl, and aryl substituents are unsubstituted or substituted;    -   Z₁ is, independently, —N(R₁₀)—C(O)—C₁₋₁₀-alkyl,        —N(R₁₀)—C(O)—(CH₂)₀₋₆—C₃₋₇-cycloalkyl,        —N(R₁₀)—C(O)—(CH₂)₀₋₆-phenyl, —N(R₁₀)—C(O)(CH₂)₁₋₆-het,        —C(O)—N(R₁₁)(R₁₂), —C(O)—O—C₁₋₁₀-alkyl,        —C(O)—O—(CH₂)₁₋₆—C₃₋₇-cycloalkyl, —C(O)—O—(CH₂)₀₋₆-phenyl,        —C(O)—O—(CH₂)₁₋₆-het, —O—C(O)—C₁₋₁₀-alkyl,        —O—C(O)—(CH₂)₁₋₆—C₃₋₇-cycloalkyl, —O—C(O)—(CH₂)₀₋₆-phenyl,        —O—C(O)—(CH₂)₁₋₆-het, wherein alkyl, cycloalkyl, and phenyl are        unsubstituted or substituted;    -   het is, independently, a 5-7 member heterocyclic ring containing        1-4 heteroatoms selected from N, O. and S, or an 8-12 member        fused ring system including at least one 5-7 member heterocyclic        ring containing 1, 2, or 3 heteroatoms selected from N, O, and        S, which heterocyclic ring or fused ring system is unsubstituted        or substituted on a carbon or nitrogen atom;    -   R₁₀ is, independently. H, —CH₃, —CF₃, —CH₂OH, or —CH₂Cl;    -   R₁₁ and R₁₂ is, independently, H, C₁₋₄-alkyl, C₃₋₇-cycloalkyl,        —(CH₂)₁₋₆—C₃₋₇-cycloakyl, (CH₂)₀₋₆-phenyl, wherein alkyl,        cycloalkyl, and phenyl are unsubstituted or substituted; or R₁₁    -   R₁₂ together with the nitrogen form het;    -   U is as shown in structure (11):

wherein:

-   -   each n is independently 0 to 5;    -   X is —CH or N;    -   R_(a) and R_(b), are independently selected from the group of        an O. S, or N atom or C₀₋₈-alkyl wherein one or more of the        carbon atoms in the alkyl chain are optionally replaced by a        heteroatom selected from O, S. or N, and where each alkyl is,        independently, either unsubstituted or substituted;    -   R_(d) is selected from: Re-Q-(R_(f))_(p)(R_(g))_(q); and        Ar₁-D-Ar₂    -   R_(e) is selected from H or any R_(c) and R_(d) together form a        cycloalkyl or het; where if R_(c) and R_(d) form a cycloalkyl or        het. R₅ is attached to the formed ring at a C or N atom;    -   each p and q is, independently. 0 or I;    -   R_(e) is selected from the group of C₁₋₈-alkyl or alkylidene,        and each R_(c) is either unsubstituted or substituted; each Q        is, independently, N, O, S, S(O), or S(O)₂;    -   each Ar₁ and Ar₂ is, independently, substituted or unsubstituted        aryl or het;    -   R_(f) and R_(g) are independently selected from H, —C1-10-alkyl,        C₁₋₁₀-alkylaryl, —OH, —O—C₁₋₁₀-alkyl, —(CH₂)₀₋₆—C₃₋₇-cycloalky,        —O—(CH₂)₀₋₆-aryl, phenyl, aryl, phenyl-phenyl, —(CH₂)₁₋₆-het,        —O—(CH₂)₁₋₆-het, —OR₁₃, —C(O)—R₁₃, —C(O)—N(R₁₃)(R₁₄),        —N(R₁₃)(R₁₄), —S—R₁₃, —S(O)—R₁₃, —S(O)₂—R₁₃, —S(O)₂—NR₁₃R₁₄,        —NR₁₃—S(O)₂—R₁₄, —S—C₁₋₁₀-alkyl, aryl-C₁₋₄-alkyl, or        het-C₁₋₄-alkyl, wherein alkyl, cycloalkyl, het, and aryl are        unsubstituted or substituted; —SO₂—C₁₋₂-alkyl,        —SO₂—C₁₋₂-alkylphenyl, —O—C₁₋₄-alkyl, or any R_(g) and R_(f)        together form a ring selected from het or aryl;    -   D is selected from the group of —CO—, —C(O)—C₁₋₇-alkylene or        arylene, —CF₂—, —O—, —S(O)_(r) where r is 0-2, 1,3-dioxalane, or        C₁₋₇-alkyl-OH, where alkyl, alkylene, or arylene are        unsubstituted or substituted with one or more halogens, OH,        —O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl, or —CF₃, or each D is,        independently, N(R_(h)) wherein each Rh is, independently, H,        unsubstituted or substituted C₁₋₇-alkyl, aryl, unsubstituted or        substituted —O—(C₁₋₇-cycloalkyl), —C(O)—C₁₋₁₀-alkyl,        —C(O)—C₀₋₁₀-alkyl-aryl, —C—O—C₀₁₋₁₀-alkyl,        —C—O—C₀₋₁₀-alkyl-aryl, —SO₂—C₁₋₁₀-alkyl, or        —SO₂—(C₀₋₁₀-alkylaryl);    -   R₆, R₇. R₈, and R₉ are independently selected from the group of        H, —C₁₋₁₀-alkyl, —C₁₋₁₀-alkoxy, aryl-C₁₋₁₀-alkoxy, —OH,        —O—C₁₋₁₀-alkyl, —(CH₂)₀₋₆—C₃₋₇-cycloalkyl, —O—(CH₂)₀₋₆-aryl,        phenyl, —(CH₂)₁₋₆-het, —O—(CH₂)₁₋₆-het, —OR₁₃, —C(O)—R₁₃,        —C(O)—N(R₁₃)(R₁₄), —N(R₁₃)(R₁₄), —S—R₁₃, —S(O)—R₁₃, —S(O)₂—R₁₃,        —S(O)₂—NR₁₃R₁₄, or —NR₁₃—S(O)₂—R₁₄, wherein each alkyl,        cycloalkyl, and aryl is unsubstituted or substituted; and any        R₆, R₇. R₈, and R₉ optionally together form a ring system;    -   R₁₃ and R₁₄ are independently selected from the group of H,        C₁₋₁₀-alkyl, —(CH₂)₀₋₆—C₃₋₇-cycloalkyl,        —(CH₂)₀₋₆—(CH)₀₋₁-(aryl)₁₋₂, —C(O)—C₁₋₁₀-alkyl,        —C(O)—(CH₂)₁₋₆—C₃₋₇-cycloalkyl. —C(O)—O—(CH₂)₀₋₆-aryl,        —C(O)—(CH₂)₀₋₆—O-fluorenyl, —C(O)—NH—(CH₂)₀₋₆-aryl,        —C(O)—(CH₂)₀₋₆-aryl, —C(O)—(CH₂)₀₋₆-het, —C(S)—C₁₋₁₀-alkyl,        —C(S)—(CH₂)₁₋₆—C₃₋₇-cycloalkyl, —C(S)—O—(CH₂)₀₋₆-aryl,        —C(S)—(CH₂)₀₋₆—O-fluorenyl, —C(S)—NH—(CH₂)₀₋₆-aryl,        —C(S)—(CH₂)₀₋₆-aryl, or —C(S)—(CH₂)₁₋₆-het, wherein each alkyl,        cycloalkyl, and aryl is unsubstituted or substituted; or any R₁₃        and R₁₄ together with a nitrogen atom form het; and    -   wherein alkyl substituents of R₁₃ and R₁₄ are unsubstituted or        substituted and when substituted, are substituted by one or more        substituents selected from C₁₋₁₀-alkyl, halogen, OH,        —O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl, and —CF₃; and substituted phenyl        or aryl of R₁₃ and R₁₄ are substituted by one or more        substituents selected from halogen, hydroxyl. C₁₋₄-alkyl,        C₁₋₄-alkoxy, nitro, —CN, —O—C(O)—C₁₋₄-alkyl, and        —C(O)—O—C₁₋₄-aryl; or a pharmaceutically acceptable salt or        hydrate thereof.

In any aspect or embodiment described herein, the AVPI tetrapeptidefragment has a chemical structure represented by a member selected fromthe group of:

wherein:

-   -   R¹ is selected from the group of H and alkyl;    -   R² is selected from the group of H and alkyl;    -   R³ is selected from the group of H, alkyl, cycloalkyl and        heterocycloalkyl;    -   R⁴ is selected from alkyl, cycloalkyl, heterocycloalkyl,        cycloalkylalkyl, heterocycloalkylalkyl, aryl, arylalkyl,        heteroaryl, heteroarylalkyl, further optionally substituted with        1-3 substituents selected from halogen, alkyl, haloalkyl,        hydroxyl, alkoxy, cyano, (hetero)cycloalkyl or (hetero)aryl, or        —C(O)NH—R⁴, where R⁴ is selected from alkyl, cycloalkyl,        heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, aryl,        arylalkyl, heteroaryl, heteroarylalkyl, further optionally        substituted with 1-3 substituents as described above;    -   R⁵ and R⁶ are independently selected from the group of H, alkyl,        cycloalkyl, heterocycloalkyl, aryl, heteroaryl or fused rings;        and    -   R⁷ is selected from the group of cycloalkyl, cycloalkylalkyl,        heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl,        heteroaryl or heteroarylalkyl, each one further optionally        substituted with 1-3 substituents selected from halogen, alkyl,        haloalkyl, hydroxyl, alkoxy, cyano, (hetero)cycloalkyl or        (hetero)aryl, or —C(O)NH—R⁴, where R⁴ is selected from alkyl,        cycloalkyl, heterocycloalkyl, cycloalkylalkyl,        heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl,        heteroarylalkyl, further optionally substituted with 1-3        substituents as described above.

In any aspect or embodiment described herein, the R⁵ and R⁶ takentogether form a pyrrolidine or a piperidine ring optionally fused to 1-2cycloalkyl, heterocycloalkyl, aryl or heteroaryl rings, each of whichcan then be further fused to another cycloalkyl, heterocycloalkyl, arylor heteroaryl ring.

In any aspect or embodiment described herein, the R³ and R⁵ takentogether form a 5-8-membered ring further optionally fused to 1-2cycloalkyl, heterocycloalkyl, aryl or heteroaryl rings.

In any aspect or embodiment described herein, the ILM is selected fromthe group consisting of:

wherein:

-   -   each of A1 and A2 is independently selected from optionally        substituted monocyclic, fused rings, aryls and hetoroaryls; and    -   R is selected from H or Me.

In any aspect or embodiment described herein, the ILM is selected fromthe group consisting of:

wherein “& 1” means ring junction stereochemistry is cis-, butconfiguration of either stereocenter is not fixed in the absolute sense.

In any aspect or embodiment described herein, the IAP E3 ubiquitinligase binding moiety is selected from the group consisting of:

In any aspect or embodiment described herein, the compound furthercomprises an independently selected second ILM attached to the ILM byway of at least one additional linker group, wherein the second ILM isan AVPI tetrapeptide fragment or an unnatural mimetic thereof and the atleast one additional linker chemically links amino acids or unnaturalmimetics thereof selected from the group consisting of valine, prolineand isoleucine, or unnatural mimetics thereof and wherein at least oneof the ILM and the second ILM is chemically linked to the linker groupchemically linked to the PTM.

In any aspect or embodiment described herein, the ILM, at least oneadditional independently selected linker group L, and the second ILM hasa structure selected from the group consisting of:

In any aspect or embodiment described herein, the ULM is selected fromthe group consisting of:

or a combination thereof,wherein:

-   -   R_(14a) is a methyl, ethyl, or hydroxymethy; and    -   X is O or H₂.

In any aspect or embodiment described herein, the PTM is selected fromthe group consisting of:

or a combination thereof, wherein

may be N-substituted.

In any aspect or embodiment described herein, the linker (L) comprises achemical structural unit represented by the formula:-(A^(L))_(q)-,wherein:

-   -   (A^(L))q is a group which is connected to at least one of a ULM        moiety, a PTM moiety, or a combination thereof;    -   q is an integer greater than or equal to 1;    -   each A^(L) is independently selected from the group consisting        of, a bond, CR^(L1)R^(L2), S, SO, SO₂, NR^(L3), SO₂NR^(L3),        SONR^(L3), CONR^(L3), NR^(L3)CONR^(L4), NR^(L3)SO₂NR^(L4), CO,        CR^(L1)═CR^(L2), C≡C, SiR^(L1)R^(L2), P(O)R^(L1), P(O)OR^(L1),        NR^(L3)C(═NCN)NR^(L4), NR^(L3)C(═NCN), NR^(L3)C(═CNO₂)NR^(L4),        C_(3-_11)cycloalkyl optionally substituted with 0-6 R^(L1)        and/or R^(L2) groups, C₃₋₁₁heterocyclyl optionally substituted        with 0-6 R^(L1) and/or R^(L2) groups, aryl optionally        substituted with 0-6 R^(L1) and/or R^(L2) groups, heteroaryl        optionally substituted with 0-6 R^(L1) and/or R^(L2) groups,        where R^(L1) or R^(L2), each independently are optionally linked        to other groups to form cycloalkyl and/or heterocyclyl moiety,        optionally substituted with 0-4 R^(L5) groups; and    -   R^(L1), R^(L2), R^(L3), R^(L4) and R^(L5) are, each        independently, H, halo, C₁₋₈alkyl, OC₁₋₈alkyl, SC₁₋₈alkyl,        NHC₁₋₈alkyl, N(C₁₋₈alkyl)₂, C₃₋₁₁cycloalkyl, aryl, heteroaryl,        C₃₋₁₁heterocyclyl, OC₁₋₈ cycloalkyl, SC₁₋₈cycloalkyl,        NHC₁₋₈cycloalkyl, N(C₁₋₈cycloalkyl)₂,        N(C₁₋₈cycloalkyl)(C₁₋₈alkyl), OH, NH₂, SH, SO₂C₁₋₈alkyl,        P(O)(OC₁₋₈alkyl)(C₁₋₈alkyl), P(O)(OC₁₋₈alkyl)₂, CC—C₁₋₈alkyl,        CCH, CH═CH(C₁₋₈alkyl), C(C₁₋₈alkyl)═CH(C₁₋₈alkyl),        C(C₁₋₈alkyl)═C(C₁₋₈alkyl)2, Si(OH)₃, Si(C₁₋₈alkyl)₃,        Si(OH)(C₁₋₈alkyl)₂, COC₁₋₈alkyl, CO₂H, halogen, CN, CF₃, CHF₂,        CH₂F, NO₂, SF₅, SO₂NHC₁₋₈alkyl, SO₂N(C₁₋₈alkyl)₂, SONHC₁₋₈alkyl,        SON(C₁₋₈alkyl)₂, CONHC₁₋₈alkyl, CON(C₁₋₈alkyl)₂,        N(C₁₋₈alkyl)CONH(C₁₋₈alkyl), N(C₁-8alkyl)CON(C₁₋₈alkyl)₂,        NHCONH(C₁₋₈alkyl), NHCON(C₁₋₈alkyl)₂, NHCONH₂,        N(C₁₋₈alkyl)SO₂NH(C₁₋₈alkyl), N(C₁₋₈alkyl) SO₂N(C₁₋₈alkyl)₂, NH        SO₂NH(C₁₋₈alkyl), NH SO₂N(C₁₋₈alkyl)₂, NH SO₂NH₂.

In any aspect or embodiment describe herein, the linker (L) is selectedfrom

wherein n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

In any aspect or embodiment described herein, the linker (L) comprises agroup represented by a general structure selected from the groupconsisting of:—N(R)—(CH₂)_(m)—O(CH₂)_(n)—O(CH₂)_(o)—O(CH₂)_(p)—O(CH₂)_(q)—O(CH₂)_(r)—OCH₂—,—O—(CH₂)_(m)—O(CH₂)_(n)—O(CH₂)_(o)O(CH₂)_(p)—O(CH₂)_(q)—O(CH₂)_(r)—OCH₂—,—O—(CH₂)_(m)—O(CH₂)_(n)—O(CH₂)_(o)—O(CH₂)_(p)—O(CH₂)_(q)—O(CH₂)_(r)—O—;—N(R)—(CH₂)_(m)—O(CH₂)_(n)—O(CH₂)_(o)—O(CH₂)_(p)—O(CH₂)_(q)—O(CH₂)_(r)—O—;—(CH₂)_(m)—O(CH₂)_(n)—O(CH₂)_(o)—O(CH₂)_(p)—O(CH₂)_(q)—O(CH₂)_(r)—O—;—(CH₂)_(m)—O(CH₂)_(n)—O(CH₂)_(o)—O(CH₂)_(p)—O(CH₂)_(q)—O(CH₂)_(r)—OCH₂—;

wherein m, n, o, p, q, and r, are independently 0, 1, 2, 3, 4, 5, 6,with the proviso that when the number is zero, there is no N—O or O—Obond, R is selected from the group H, methyl and ethyl, and X isselected from the group H and F;

wherein each n and m of the linker can independently be 0, 1, 2, 3, 4,5, 6.

In any aspect or embodiment described herein, the linker (L) is selectedfrom the group consisting of:

wherein each m and n is independently 0, 1, 2, 3, 4, 5, or 6.

In any aspect or embodiment described herein, the linker (L) is selectedfrom the group consisting of:

wherein each m, n, o, p, q, and r is independently 0, 1, 2, 3, 4, 5, 6,or 7.

In any aspect or embodiment described herein, L is selected from thegroup consisting of:

In additional embodiments, the linker (L) comprises a structure selectedfrom, but not limited to the structure shown below, where a dashed lineindicates the attachment point to the PTM or ULM moieties.

wherein:

-   -   W^(L1) and W^(L2) are each independently a 4-8 membered ring        with 0-4 heteroatoms, optionally substituted with R^(Q), each        R^(Q) is independently a H, halo, OH, CN, CF₃, C₁-C₆ alkyl        (linear, branched, optionally substituted), C₁-C₆ alkoxy        (linear, branched, optionally substituted), or 2 R^(Q) groups        taken together with the atom they are attached to, form a 4-8        membered ring system containing 0-4 heteroatoms;    -   Y^(L1) is each independently a bond, C₁-C₆ alkyl (linear,        branched, optionally substituted) and optionally one or more C        atoms are replaced with O; or C₁-C₆ alkoxy (linear, branched,        optionally substituted);    -   n is 0-10; and    -   a dashed line indicates the attachment point to the PTM or ULM        moieties.

In additional embodiments, the linker (L) comprises a structure selectedfrom, but not limited to the structure shown below, where a dashed lineindicates the attachment point to the PTM or ULM moieties.

wherein:

-   -   W^(L1) and W^(L2) are each independently aryl, heteroaryl,        cyclic, heterocyclic, C₁₋₆ alkyl, bicyclic, biaryl,        biheteroaryl, or biheterocyclic, each optionally substituted        with R^(Q), each R^(Q) is independently a H, halo, OH, CN, CF₃,        hydroxyl, nitro, C≡CH, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁-C₆ alkyl        (linear, branched, optionally substituted), C₁-C₆ alkoxy        (linear, branched, optionally substituted), OC₁₋₃alkyl        (optionally substituted by 1 or more —F), OH, NH₂,        NR^(Y1)R^(Y2), CN, or 2 R^(Q) groups taken together with the        atom they are attached to, form a 4-8 membered ring system        containing 0-4 heteroatoms;    -   Y^(L1) is each independently a bond, NR^(YL1), O, S, NR^(YL2),        CR^(YL1)R^(YL2), C═O, C═S, SO, SO₂, C₁-C₆alkyl (linear,        branched, optionally substituted) and optionally one or more C        atoms are replaced with O; C₁-C₆ alkoxy (linear, branched,        optionally substituted);    -   Q^(L) is a 3-6 membered alicyclic or aromatic ring with 0-4        heteroatoms, optionally bridged, optionally substituted with 0-6        R^(Q), each R^(Q) is independently H, C₁₋₆ alkyl (linear,        branched, optionally substituted by 1 or more halo, C₁₋₆        alkoxyl), or 2 R^(Q) groups taken together with the atom they        are attached to, form a 3-8 membered ring system containing 0-2        heteroatoms);    -   R^(YL1), R^(YL2) are each independently H, OH, C₁₋₆ alkyl        (linear, branched, optionally substituted by 1 or more halo,        C₁₋₆ alkoxyl), or R¹, R² together with the atom they are        attached to, form a 3-8 membered ring system containing 0-2        heteroatoms);    -   n is 0-10; and    -   a dashed line indicates the attachment point to the PTM or ULM        moieties.

In any aspect or embodiment described herein, the linker (L) is apolyethylenoxy group optionally substituted with aryl or phenylcomprising from 1 to 10 ethylene glycol units.

In any aspect or embodiment described herein, the compound comprisesmultiple ULMs, multiple PTMs, multiple linkers or any combinationsthereof.

In any aspect or embodiment described herein, the compound is has achemical structure selected from exemplary compounds 1-119 (i.e., acompound of Table 1 or 2), including salts, prodrugs, polymorphs,analogs, derivatives, and deuterated forms thereof.

In another aspect, the present disclosure provides a composition thatcomprises an effective amount of a bifunctional compound of the presentdisclosure, and a pharmaceutically acceptable carrier.

In any aspect or embodiment described herein, the composition furthercomprises at least one of additional bioactive agent or anotherbifunctional compound of the present disclosure.

In any aspect or embodiment described herein, the additional bioactiveagent is anti-cancer agent.

In a further aspect, the present disclosure provides a composition thatcomprises a pharmaceutically acceptable carrier and an effective amountof at least one compound of the present disclosure for treating adisease or disorder in a subject, the method comprising administeringthe composition to a subject in need thereof, wherein the compound iseffective in treating or ameliorating at least one symptom of thedisease or disorder.

In any aspect or embodiment described herein, the disease or disorder isassociated with EZH2 accumulation and aggregation.

In any aspect or embodiment described herein, the disease or disorder iscancer associated with EZH2 accumulation and aggregation.

In any aspect or embodiment described herein, the disease or disorder iscancer.

What is claimed is:
 1. A compound having the chemical structure:ULM-L-PTM, or a pharmaceutically acceptable salt thereof, wherein: (a)the ULM is:

wherein: W is CH₂ or C═O; A is H;

represents a bond that may be stereospecific or non-stereospecific; n is1; and R is a bond to the chemical linking moiety or NHR′ covalentlyjoined to the chemical linking moiety; R′ is alkyl; (b) the L is achemical linking moiety connecting the ULM and the PTM which comprises(1) a chemical structural unit represented by the formula:—(CH₂)m-O(CH₂)n-O(CH₂)o-O(CH₂)p-O(CH₂)q-O(CH₂)r-O—,—NH—(CH₂)m-O(CH₂)n-O(CH₂)o-O(CH₂)p-O(CH₂)q-O(CH₂)r-O—;

 wherein: each m, o, p, q, and r of the chemical linking moiety areindependently 0, 1, 2, 3, 4, 5, 6, with the proviso that when the numberis zero, there is no N—O or O—O bond; n of the chemical linking moietyis 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; or (2) a polyethylenoxy groupcomprising 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 ethylene glycol units; and(c) the PTM is PTM-I-1, PTM-IVa-1, or PTM-IVb-1:

wherein: W_(PTM) and X_(PTM) are independently C or N; Y_(PTM) andZ_(PTM) are CH; X_(PTM1) is NH or O; X_(PTM2) is absent; R_(PTM) ismethyl or methoxy; R_(PTM5) is methyl; and

indicates a covalent linkage to the chemical linking moiety.
 2. Thecompound according to claim 1, wherein L is:


3. The compound according to claim 1, wherein the chemical linkingmoiety (L) is a polyethylenoxy group comprising 1, 2, 3, 4, 5, 6, 7, 8,9, or 10 ethylene glycol units.
 4. A compound, wherein the compound is:

or a pharmaceutically acceptable salt thereof.
 5. A pharmaceuticalcomposition comprising a compound of claim 1, and a pharmaceuticallyacceptable carrier.
 6. The pharmaceutical composition of claim 5,wherein the composition further comprises at least one additionalbioactive agent.
 7. The pharmaceutical composition of claim 6, whereinthe additional bioactive agent is an anti-cancer agent.
 8. A method oftreating a disease or disorder, associated with EZH2 accumulation andaggregation the method comprising administering a compound of claim 1 toa subject.
 9. The method of claim 8, wherein the disease or disorder iscancer.
 10. The method of claim 8, wherein the disease or disorder isbreast cancer, prostate cancer, bladder cancer, uterine cancer, renalcancer, melanoma, and/or lymphoma.
 11. A pharmaceutical compositioncomprising a compound of claim 4, and a pharmaceutically acceptablecarrier.
 12. The pharmaceutical composition of claim 11, wherein thecomposition further comprises at least one additional bioactive agent.13. The pharmaceutical composition of claim 12, wherein the additionalbioactive agent is an anti-cancer agent.
 14. A method of treating adisease or disorder, associated with EZH2 accumulation and aggregationthe method comprising administering a compound of claim 4 to a subject.15. The method of claim 14, wherein the disease or disorder is cancer.16. The method of claim 14, wherein the disease or disorder is breastcancer, prostate cancer, bladder cancer, uterine cancer, renal cancer,melanoma, and/or lymphoma.